Cyclol
Encyclopedia
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
of a folded
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
, globular
Globular protein
Globular proteins, or spheroproteins are one of the two main protein classes, comprising "globe"-like proteins that are more or less soluble in aqueous solutions...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
. It was developed by Dorothy Wrinch
Dorothy Maud Wrinch
Dorothy Maud Wrinch was a mathematician and biochemical theorist best known for her attempt to deduce protein structure using mathematical principles....
in the late 1930s, and was based on three assumptions. Firstly, the hypothesis assumes that two peptide groups
Peptide bond
This article is about the peptide link found within biological molecules, such as proteins. A similar article for synthetic molecules is being created...
can be crosslinked by a cyclol reaction (Figure 1); these crosslinks are covalent analogs of non-covalent hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
s between peptide groups. These reactions have been observed in the ergopeptides
Ergoline
Ergoline is a chemical compound whose structural skeleton is contained in a diverse range of alkaloids including a few psychedelic drugs . Ergoline derivatives are used clinically for the purpose of vasoconstriction and in the treatment of migraines and Parkinson's disease...
and other compounds. Secondly, it assumes that, under some conditions, amino acids will naturally make the maximum possible number of cyclol crosslinks, resulting in cyclol molecules (Figure 2) and cyclol fabrics (Figure 3). These cyclol molecules and fabrics have never been observed. Finally, the hypothesis assumes that globular proteins have a tertiary structure
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
corresponding to Platonic solid
Platonic solid
In geometry, a Platonic solid is a convex polyhedron that is regular, in the sense of a regular polygon. Specifically, the faces of a Platonic solid are congruent regular polygons, with the same number of faces meeting at each vertex; thus, all its edges are congruent, as are its vertices and...
s and semiregular polyhedra
Semiregular polyhedron
The term semiregular polyhedron is used variously by different authors.In its original definition, it is a polyhedron with regular faces and a symmetry group which is transitive on its vertices, which is more commonly referred to today as a uniform polyhedron...
formed of cyclol fabrics with no free edges. Such "closed cyclol" molecules have not been observed either.
Although later data demonstrated that this original model for the structure of globular proteins
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
needed to be amended, several elements of the cyclol model were verified, such as the cyclol reaction itself and the hypothesis that hydrophobic interactions are chiefly responsible for protein folding
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
. The cyclol hypothesis stimulated many scientists to research questions in protein structure and chemistry, and was a precursor of the more accurate models hypothesized for the DNA double helix
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
and protein secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
. The proposal and testing of the cyclol model also provides an excellent illustration of empirical
Empirical
The word empirical denotes information gained by means of observation or experimentation. Empirical data are data produced by an experiment or observation....
falsifiability
Falsifiability
Falsifiability or refutability of an assertion, hypothesis or theory is the logical possibility that it can be contradicted by an observation or the outcome of a physical experiment...
acting as part of the scientific method
Scientific method
Scientific method refers to a body of techniques for investigating phenomena, acquiring new knowledge, or correcting and integrating previous knowledge. To be termed scientific, a method of inquiry must be based on gathering empirical and measurable evidence subject to specific principles of...
.
Historical context
By the mid-1930s, analytical ultracentrifugation studies by Theodor SvedbergTheodor Svedberg
Theodor H. E. Svedberg was a Swedish chemist and Nobel laureate, active at Uppsala University. His work with colloids supported the theories of Brownian motion put forward by Einstein and the Polish geophysicist Marian Smoluchowski...
had shown that proteins had a well-defined chemical structure, and were not aggregations of small molecules. The same studies appeared to show that the molecular weight of proteins fell into a few well-defined classes related by integers, such as Mw = 2p3q Da
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
, where p and q are nonnegative integers. However, it was difficult to determine the exact molecular weight and number of amino acids in a protein. Svedberg had also shown that a change in solution conditions could cause a protein to disassemble into small subunits, now known as a change in quaternary structure
Quaternary structure
In biochemistry, quaternary structure is the arrangement of multiple folded protein or coiling protein molecules in a multi-subunit complex.-Description and examples:...
.
The chemical structure
Primary structure
The primary structure of peptides and proteins refers to the linear sequence of its amino acid structural units. The term "primary structure" was first coined by Linderstrøm-Lang in 1951...
of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s was still under debate at that time. The most accepted (and ultimately correct) hypothesis was that proteins are linear polypeptides, i.e., unbranched polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
s of amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s linked by peptide bond
Peptide bond
This article is about the peptide link found within biological molecules, such as proteins. A similar article for synthetic molecules is being created...
s. However, a typical protein is remarkably long — hundreds of amino-acid residues
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
— and several distinguished scientists were unsure whether such long, linear macromolecule
Macromolecule
A macromolecule is a very large molecule commonly created by some form of polymerization. In biochemistry, the term is applied to the four conventional biopolymers , as well as non-polymeric molecules with large molecular mass such as macrocycles...
s could be stable in solution. Further doubts about the polypeptide nature of proteins
Primary structure
The primary structure of peptides and proteins refers to the linear sequence of its amino acid structural units. The term "primary structure" was first coined by Linderstrøm-Lang in 1951...
arose because some enzymes were observed to cleave proteins but not peptides, whereas other enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s cleave peptides but not folded proteins. Attempts to synthesize proteins in the test-tube were unsuccessful, mainly due to the chirality
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....
of amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s; naturally occurring proteins are composed of only left-handed amino acids. Hence, alternative chemical models of proteins were considered, such as the diketopiperazine hypothesis of Emil Abderhalden
Emil Abderhalden
Emil Abderhalden was a Swiss biochemist and physiologist. His main findings, though disputed already in the 1920s, were not finally rejected until the late 1990s. Whether his misleading findings were based on fraud or simply the result of a lack of scientific rigor remains unclear...
. However, no alternative model had yet explained why proteins yield only amino acids and peptides upon hydrolysis and proteolysis. As clarified by Linderstrøm-Lang
Kaj Ulrik Linderstrom-Lang
Kaj Ulrik Linderstrøm-Lang was a Danish protein scientist, who was the director of the Carlsberg Laboratory from 1939 until his death....
, these proteolysis data showed that denatured proteins
Denaturation (biochemistry)
Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
were polypeptides, but no data had yet been obtained about the structure of folded proteins; thus, denaturation could involve a chemical change that converted folded proteins into polypeptides.
The process of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
denaturation
Denaturation (biochemistry)
Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
(as distinguished from coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
) had been discovered in 1910 by Harriette Chick
Harriette Chick
Dame Harriette Chick, DBE was a notable British protein scientist and nutritionist. Educated at Notting Hill & Ealing High School, She served as secretary of the League of Nations health section committee on the physiological bases of nutrition from 1934 to 1937...
and Charles Martin
Charles James Martin
Charles James Martin, FRS, FRCS was a British scientist who did seminal work on protein denaturation, nutrition, snake toxins and other medical topics...
, but its nature was still mysterious. Tim Anson
Mortimer Louis Anson
Mortimer Louis Anson was an early protein scientist.He is famous for having proposed that protein folding was areversible, two-state reaction, and for being the foundingeditor of the journal Advances in Protein Chemistry....
and Alfred Mirsky
Alfred Mirsky
Alfred Ezra Mirsky was an American pioneer in molecular biology.Mirsky graduated from Harvard College in 1922, after which he studied for two years at the Columbia University College of Physicians and Surgeons until 1924 when he moved to the University of Cambridge on a US National Research...
had shown that denaturation was a reversible, two-state process that results in many chemical groups becoming available for chemical reactions, including cleavage by enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s. In 1929, Hsien Wu
Hsien Wu
Hsien Wu was an early protein scientist who was the first to propose that protein denaturation was a purely conformational change, i.e., corresponded to protein unfolding and not to some chemical alteration of the protein...
hypothesized correctly that denaturation corresponded to protein unfolding, a purely conformational change that resulted in the exposure of amino-acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
side chains to the solvent. Wu's hypothesis was also advanced independently in 1936 by Mirsky and Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
. Nevertheless, protein scientists could not exclude the possibility that denaturation corresponded to a chemical change in the protein structure, a hypothesis that was considered a (distant) possibility until the 1950s.
X-ray crystallography
X-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
had just begun as a discipline in 1911, and had advanced relatively rapidly from simple salt crystals to crystals of complex molecules such as cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
. However, even the smallest proteins have over 1000 atoms, which makes determining their structure far more complex. In 1934, Dorothy Crowfoot Hodgkin
Dorothy Crowfoot Hodgkin
Dorothy Mary Hodgkin OM, FRS , née Crowfoot, was a British chemist, credited with the development of protein crystallography....
had taken crystallographic data on the structure of the small protein, insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, although the structure of that and other proteins were not solved until the late 1960s. However, pioneering X-ray
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...
fiber diffraction
Fiber diffraction
Fiber diffraction is a subarea of scattering, an area in which molecular structure is determined from scattering data . In fiber diffraction the scattering pattern does not change, as the sample is rotated about a unique axis...
data had been collected in the early 1930s for many natural fibrous protein
Fibrous protein
Scleroproteins, or fibrous proteins, constitute one of the three main classes of proteins, alongside globular proteins and conjugated proteins.Keratin, collagen, elastin, and fibroin are all scleroproteins...
s such as wool and hair by William Astbury
William Astbury
William Thomas Astbury FRS was an English physicist and molecular biologist who made pioneering X-ray diffraction studies of biological molecules. His work on keratin provided the foundation for Linus Pauling's discovery of the alpha helix...
, who proposed rudimentary models of secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
elements such as the alpha helix
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
and the beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
.
Since protein structure
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
was so poorly understood in the 1930s, the physical interactions responsible for stabilizing that structure were likewise unknown. Astbury
William Astbury
William Thomas Astbury FRS was an English physicist and molecular biologist who made pioneering X-ray diffraction studies of biological molecules. His work on keratin provided the foundation for Linus Pauling's discovery of the alpha helix...
hypothesized that the structure of fibrous protein
Fibrous protein
Scleroproteins, or fibrous proteins, constitute one of the three main classes of proteins, alongside globular proteins and conjugated proteins.Keratin, collagen, elastin, and fibroin are all scleroproteins...
s was stabilized by hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
s in β-sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
s. The idea that globular protein
Globular protein
Globular proteins, or spheroproteins are one of the two main protein classes, comprising "globe"-like proteins that are more or less soluble in aqueous solutions...
s are also stabilized by hydrogen bonds was proposed by Dorothy Jordan Lloyd
Dorothy Jordan Lloyd
Dorothy Jordan Lloyd was an early protein scientist who studied the interactions of water with proteins, particularly gelatin. She was also Director of the British Leather Manufacturers' Research Association...
in 1932, and championed later by Alfred Mirsky
Alfred Mirsky
Alfred Ezra Mirsky was an American pioneer in molecular biology.Mirsky graduated from Harvard College in 1922, after which he studied for two years at the Columbia University College of Physicians and Surgeons until 1924 when he moved to the University of Cambridge on a US National Research...
and Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
. At a 1933 lecture by Astbury to the Oxford Junior Scientific Society, physicist Frederick Frank
Frederick Charles Frank
Sir Frederick Charles Frank FRS was a British theoretical physicist.He was born in Durban, South Africa, although his parents returned to England soon afterwards...
suggested that the fibrous protein α-keratin might be stabilized by an alternative mechanism, namely, covalent crosslinking of the peptide bond
Peptide bond
This article is about the peptide link found within biological molecules, such as proteins. A similar article for synthetic molecules is being created...
s by the cyclol reaction above. The cyclol crosslink draws the two peptide groups close together; the N and C atoms are separated by ~1.5 Å
Ångström
The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....
, whereas they are separated by ~3 Å
Ångström
The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....
in a typical hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
. The idea intrigued J. D. Bernal
J. D. Bernal
John Desmond Bernal FRS was one of Britain’s best known and most controversial scientists, called "Sage" by his friends, and known for pioneering X-ray crystallography in molecular biology.-Origin and education:His family was Irish, of mixed Italian and Spanish/Portuguese Sephardic Jewish origin...
, who suggested it to the mathematician Dorothy Wrinch
Dorothy Maud Wrinch
Dorothy Maud Wrinch was a mathematician and biochemical theorist best known for her attempt to deduce protein structure using mathematical principles....
as possibly useful in understanding protein structure.
Basic theory
Dorothy Maud Wrinch
Dorothy Maud Wrinch was a mathematician and biochemical theorist best known for her attempt to deduce protein structure using mathematical principles....
developed this suggestion into a full-fledged model of protein structure
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
. The basic cyclol model was laid out in her first paper (1936). She noted the possibility that polypeptides might cyclize to form closed rings (true
Cyclic peptide
Cyclic peptides are polypeptide chains whose amino and carboxyl termini are themselves linked together with a peptide bond that forms a circular chain. A number of cyclic peptides have been discovered in nature and they can range anywhere from just a few amino acids in length, to hundreds...
) and that these rings might form internal crosslinks through the cyclol reaction (also true, although rare). Assuming that the cyclol form of the peptide bond
Peptide bond
This article is about the peptide link found within biological molecules, such as proteins. A similar article for synthetic molecules is being created...
could be more stable than the amide form, Wrinch concluded that certain cyclic peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
s would naturally make the maximal number of cyclol bonds (such as cyclol 6, Figure 2). Such cyclol molecules would have hexagonal symmetry, if the chemical bond
Chemical bond
A chemical bond is an attraction between atoms that allows the formation of chemical substances that contain two or more atoms. The bond is caused by the electromagnetic force attraction between opposite charges, either between electrons and nuclei, or as the result of a dipole attraction...
s were taken as having the same length, roughly 1.5 Å
Ångström
The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....
; for comparison, the N-C and C-C bonds have the lengths 1.42 Å
Ångström
The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....
and 1.54 Å
Ångström
The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....
, respectively.
These rings can be extended indefinitely to form a cyclol fabric (Figure 3). Such fabrics exhibit a long-range, quasi-crystalline order that Wrinch felt was likely in proteins, since they must pack hundreds of residues densely. Another interesting feature of such molecules and fabrics is that their amino-acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
side chains point axially upwards from only one face; the opposite face has no side chains. Thus, one face is completely independent of the primary sequence of the peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
, which Wrinch conjectured might account for sequence-independent properties of proteins.
In her initial article, Wrinch stated clearly that the cyclol model was merely a working hypothesis, a potentially valid model of proteins that would have to be checked. Her goals in this article and its successors were to propose a well-defined testable model, to work out the consequences of its assumptions and to make predictions that could be tested experimentally. In these goals, she succeeded; however, within a few years, experiments and further modeling showed that the cyclol hypothesis was untenable as a model for globular proteins.
Stabilizing energies
Irving Langmuir
Irving Langmuir was an American chemist and physicist. His most noted publication was the famous 1919 article "The Arrangement of Electrons in Atoms and Molecules" in which, building on Gilbert N. Lewis's cubical atom theory and Walther Kossel's chemical bonding theory, he outlined his...
hypothesized that hydrophobic association of nonpolar sidechains provides stabilizing energy to overcome the energetic cost of the cyclol reactions.
The lability of the cyclol bond was seen as an advantage of the model, since it provided a natural explanation for the properties of denaturation
Denaturation (biochemistry)
Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
; reversion of cyclol bonds to their more stable amide form would open up the structure and allows those bonds to be attacked by protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s, consistent with experiment. Early studies showed that proteins denatured
Denaturation (biochemistry)
Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
by pressure
Pressure
Pressure is the force per unit area applied in a direction perpendicular to the surface of an object. Gauge pressure is the pressure relative to the local atmospheric or ambient pressure.- Definition :...
are often in a different state than the same proteins denatured by high temperature
Temperature
Temperature is a physical property of matter that quantitatively expresses the common notions of hot and cold. Objects of low temperature are cold, while various degrees of higher temperatures are referred to as warm or hot...
, which was interpreted as possibly supporting the cyclol model of denaturation.
The Langmuir-Wrinch hypothesis of hydrophobic stabilization shared in the downfall of the cyclol model, owing mainly to the influence of Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
, who favored the hypothesis that protein structure was stabilized by hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
s. Another twenty years had to pass before hydrophobic interactions were recognized as the chief driving force in protein folding.
Steric complementarity
In her third paper on cyclols (1936), Wrinch noted that many "physiologically active" substances such as steroidSteroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
s are composed of fused hexagonal rings of carbon atoms and, thus, might be sterically complementary to the face of cyclol molecules without the amino-acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
side chains. Wrinch proposed that steric complementarity was one of chief factors in determining whether a small molecule would bind to a protein.
Wrinch speculated that proteins are responsible for the synthesis of all biological molecules. Noting that cells digest their proteins only under extreme starvation conditions, Wrinch further speculated that life could not exist without proteins.
Hybrid models
From the beginning, the cyclol reaction was considered as a covalent analog of the hydrogen bondHydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
. Therefore, it was natural to consider hybrid models with both types of bonds. This was the subject of Wrinch's fourth paper on the cyclol model (1936), written together with Dorothy Jordan Lloyd
Dorothy Jordan Lloyd
Dorothy Jordan Lloyd was an early protein scientist who studied the interactions of water with proteins, particularly gelatin. She was also Director of the British Leather Manufacturers' Research Association...
, who first proposed that globular proteins are stabilized by hydrogen bonds. A follow-up paper was written in 1937 that referenced other researchers on hydrogen bonding in proteins, such as Maurice Loyal Huggins
Maurice Loyal Huggins
Maurice Loyal Huggins was a scientist who independently conceived the idea of hydrogen bonding and who was an early advocate for their role in stabilizing protein secondary structure...
and Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
.
Wrinch also wrote a paper with William Astbury
William Astbury
William Thomas Astbury FRS was an English physicist and molecular biologist who made pioneering X-ray diffraction studies of biological molecules. His work on keratin provided the foundation for Linus Pauling's discovery of the alpha helix...
, noting the possibility of a keto-enol isomerization of the >CαHα and an amide carbonyl group >C=O, producing a crosslink >Cα-C(OHα)< and again converting the oxygen to a hydroxyl group. Such reactions could yield five-membered rings, whereas the classic cyclol hypothesis produces six-membered rings. This keto-enol crosslink hypothesis was not developed much further.
Space-enclosing fabrics
Dihedral angle
In geometry, a dihedral or torsion angle is the angle between two planes.The dihedral angle of two planes can be seen by looking at the planes "edge on", i.e., along their line of intersection...
between the planes equals the tetrahedral bond angle δ = arccos(-1/3) ≈ 109.47°.
A large variety of closed polyhedra meeting this criterion can be constructed, of which the simplest are the truncated tetrahedron
Truncated tetrahedron
In geometry, the truncated tetrahedron is an Archimedean solid. It has 4 regular hexagonal faces, 4 regular triangular faces, 12 vertices and 18 edges.- Area and volume :...
, the truncated octahedron
Truncated octahedron
In geometry, the truncated octahedron is an Archimedean solid. It has 14 faces , 36 edges, and 24 vertices. Since each of its faces has point symmetry the truncated octahedron is a zonohedron....
, and the octahedron
Octahedron
In geometry, an octahedron is a polyhedron with eight faces. A regular octahedron is a Platonic solid composed of eight equilateral triangles, four of which meet at each vertex....
, which are Platonic solid
Platonic solid
In geometry, a Platonic solid is a convex polyhedron that is regular, in the sense of a regular polygon. Specifically, the faces of a Platonic solid are congruent regular polygons, with the same number of faces meeting at each vertex; thus, all its edges are congruent, as are its vertices and...
s or semiregular polyhedra
Semiregular polyhedron
The term semiregular polyhedron is used variously by different authors.In its original definition, it is a polyhedron with regular faces and a symmetry group which is transitive on its vertices, which is more commonly referred to today as a uniform polyhedron...
. Considering the first series of "closed cyclols" (those modeled on the truncated tetrahedron), Wrinch showed that their number of amino acids increased quadratically
Quadratic growth
In mathematics, a function or sequence is said to exhibit quadratic growth when its values are proportional to the square of the function argument or sequence position, in the limit as the argument or sequence position goes to infinity...
as 72n2, where n is the index of the closed cyclol Cn. Thus, the C1 cyclol has 72 residues, the C2 cyclol has 288 residues, etc. Preliminary experimental support for this prediction came from Max Bergmann
Max Bergmann
Max Bergmann was a Jewish-German biochemist. He was the first to use the Carboxybenzyl protecting group for the synthesis of oligopeptides.-Life and work:Bergmann was born in Fürth, Bavaria, Germany on February 12, 1886....
and Carl Niemann
Carl Niemann
Carl George Niemann was an American biochemist who worked extensively on the chemistry and structure of proteins, publishing over 260 research papers...
, whose amino-acid analyses suggested that proteins were composed of integer multiples of 288 amino-acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues (n=2). More generally, the cyclol model of globular proteins accounted for the early analytical ultracentrifugation results of Theodor Svedberg
Theodor Svedberg
Theodor H. E. Svedberg was a Swedish chemist and Nobel laureate, active at Uppsala University. His work with colloids supported the theories of Brownian motion put forward by Einstein and the Polish geophysicist Marian Smoluchowski...
, which suggested that the molecular weights of proteins fell into a few classes related by integers.
The cyclol model was consistent with the general properties then attributed to folded proteins. (1) Centrifugation studies had shown that folded proteins were significantly denser than water (~1.4 g
Gram
The gram is a metric system unit of mass....
/mL
Litér
- External links :*...
) and, thus, tightly packed; Wrinch assumed that dense packing should imply regular packing. (2) Despite their large size, some proteins crystallize readily into symmetric crystals, consistent with the idea of symmetric faces that match up upon association. (3) Proteins bind metal ions; since metal-binding sites must have specific bond geometries (e.g., octahedral), it was plausible to assume that the entire protein also had similarly crystalline geometry. (4) As described above, the cyclol model provided a simple chemical explanation of denaturation
Denaturation (biochemistry)
Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
and the difficulty of cleaving folded proteins with proteases. (5) Proteins were assumed to be responsible for the synthesis of all biological molecules, including other proteins. Wrinch noted that a fixed, uniform structure would be useful for proteins in templating their own synthesis, analogous to the Watson
James D. Watson
James Dewey Watson is an American molecular biologist, geneticist, and zoologist, best known as one of the co-discoverers of the structure of DNA in 1953 with Francis Crick...
-Francis Crick
Francis Crick
Francis Harry Compton Crick OM FRS was an English molecular biologist, biophysicist, and neuroscientist, and most noted for being one of two co-discoverers of the structure of the DNA molecule in 1953, together with James D. Watson...
concept of DNA templating its own replication. Given that many biological molecules such as sugars
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
and sterol
Sterol
Sterols, also known as steroid alcohols, are a subgroup of the steroids and an important class of organic molecules. They occur naturally in plants, animals, and fungi, with the most familiar type of animal sterol being cholesterol...
s have a hexagonal structure, it was plausible to assume that their synthesizing proteins likewise had a hexagonal structure. Wrinch summarized her model and the supporting molecular-weight experimental data in three review articles.
Predicted protein structures
Having proposed a model of globular proteins, Wrinch investigated whether it was consistent with the available structural data. She hypothesized that bovine tuberculin protein (523) was a C1 closed cyclol consisting of 72 residues and that the digestive enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
pepsin
Pepsin
Pepsin is an enzyme whose precursor form is released by the chief cells in the stomach and that degrades food proteins into peptides. It was discovered in 1836 by Theodor Schwann who also coined its name from the Greek word pepsis, meaning digestion...
was a C2 closed cyclol of 288 residues. These residue-number predictions were difficult to verify, since the methods then available to measure the mass of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s were inaccurate, such as analytical ultracentrifugation and chemical methods.
Wrinch also predicted that insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
was a C2 closed cyclol consisting of 288 residues. Limited X-ray crystallographic data were available for insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
which Wrinch interpreted as "confirming" her model. However, this interpretation drew rather severe criticism for being premature. Careful studies of the Patterson diagrams of insulin taken by Dorothy Crowfoot Hodgkin
Dorothy Crowfoot Hodgkin
Dorothy Mary Hodgkin OM, FRS , née Crowfoot, was a British chemist, credited with the development of protein crystallography....
showed that they were roughly consistent with the cyclol model; however, the agreement was not good enough to claim that the cyclol model was confirmed.
Downfall
Hans Neurath
Hans Neurath was a biochemist, a leader in protein chemistry and the founding chairman of the Department of Biochemistry at the University of Washington in Seattle.-Early life:...
and Henry Bull showed that the dense packing of side chains in the cyclol fabric was inconsistent with the experimental density observed in protein films. Maurice Huggins
Maurice Loyal Huggins
Maurice Loyal Huggins was a scientist who independently conceived the idea of hydrogen bonding and who was an early advocate for their role in stabilizing protein secondary structure...
calculated that several non-bonded atoms of the cyclol fabric would approach more closely than allowed by their van der Waals radii
Van der Waals radius
The van der Waals radius, r, of an atom is the radius of an imaginary hard sphere which can be used to model the atom for many purposes. It is named after Johannes Diderik van der Waals, winner of the 1910 Nobel Prize in Physics, as he was the first to recognise that atoms had a finite size and to...
; for example, the inner Hα and Cα atoms of the lacunae would be separated by only 1.68 Å
Ångström
The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....
(Figure 5). Haurowitz showed chemically that the outside of proteins could not have a large number of hydroxyl groups, a key prediction of the cyclol model, whereas Meyer and Hohenemser showed that cyclol condensations of amino acids did not exist even in minute quantities as a transition state. More general chemical arguments against the cyclol model were given by Bergmann and Niemann and by Neuberger. Infrared spectroscopic data showed that the number of carbonyl groups in a protein did not change upon hydrolysis, and that intact, folded proteins have a full complement of amide carbonyl groups; both observations contradict the cyclol hypothesis that such carbonyls are converted to hydroxyl groups in folded proteins. Finally, proteins were known to contain proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
in significant quantities (typically 5%); since proline lacks the amide hydrogen and its nitrogen already forms three covalent bonds, proline seems incapable of the cyclol reaction and of being incorporated into a cyclol fabric. An encyclopedic summary of the chemical and structural evidence against the cyclol model was given by Pauling and Niemann. Moreover, a supporting piece of evidence — the result that all proteins contain an integer multiple of 288 amino-acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues — was likewise shown to be incorrect in 1939.
Wrinch replied to the steric-clash, free-energy, chemical and residue-number criticisms of the cyclol model. On steric clashes, she noted that small deformations of the bond angles and bond lengths would allow these steric clashes to be relieved, or at least reduced to a reasonable level. She noted that distances between non-bonded groups within a single molecule can be shorter than expected from their van der Waals radii
Van der Waals radius
The van der Waals radius, r, of an atom is the radius of an imaginary hard sphere which can be used to model the atom for many purposes. It is named after Johannes Diderik van der Waals, winner of the 1910 Nobel Prize in Physics, as he was the first to recognise that atoms had a finite size and to...
, e.g., the 2.93 Å
Ångström
The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....
distance between methyl groups in hexamethylbenzene. Regarding the free-energy penalty for the cyclol reaction, Wrinch disagreed with Pauling's calculations and stated that too little was known of intramolecular energies to rule out the cyclol model on that basis alone. In reply to the chemical criticisms, Wrinch suggested that the model compounds and simple bimolecular reactions studied need not pertain to the cyclol model, and that steric hindrance may have prevented the surface hydroxyl groups from reacting. On the residue-number criticism, Wrinch extended her model to allow for other numbers of residues. In particular, she produced a "minimal" closed cyclol of only 48 residues, and, on that (incorrect) basis, may have been the first to suggest that the insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
monomer had a molecular weight of roughly 6000 Da
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
.
Therefore, she maintained that the cyclol model of globular proteins was still potentially viable and even proposed the cyclol fabric as a component of the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
. However, most protein scientists ceased to believe in it and Wrinch turned her scientific attention to mathematical problems in X-ray crystallography
X-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
, to which she contributed significantly. One exception was physicist Gladys Anslow
Gladys Anslow
Gladys Amelia Anslow was a physicist who spent her career at Smith College.Born in Springfield, Massachusetts, Anslow attended Springfield Central High School and entered Smith College in 1909.She earned her A.B. in 1914 after studying physics beginning her second year under Professor Frank Allan...
, Wrinch's colleague at Smith College
Smith College
Smith College is a private, independent women's liberal arts college located in Northampton, Massachusetts. It is the largest member of the Seven Sisters...
, who studied the ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
absorption
Absorption (electromagnetic radiation)
In physics, absorption of electromagnetic radiation is the way by which the energy of a photon is taken up by matter, typically the electrons of an atom. Thus, the electromagnetic energy is transformed to other forms of energy for example, to heat. The absorption of light during wave propagation is...
spectra of proteins and peptides in the 1940s and allowed for the possibility of cyclols in interpreting her results. As the sequence
Primary structure
The primary structure of peptides and proteins refers to the linear sequence of its amino acid structural units. The term "primary structure" was first coined by Linderstrøm-Lang in 1951...
of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
began to be determined by Frederick Sanger
Frederick Sanger
Frederick Sanger, OM, CH, CBE, FRS is an English biochemist and a two-time Nobel laureate in chemistry, the only person to have been so. In 1958 he was awarded a Nobel prize in chemistry "for his work on the structure of proteins, especially that of insulin"...
, Anslow published a three-dimensional cyclol model with sidechains, based on the backbone of Wrinch's 1948 "minimal cyclol" model.
Partial redemption
J. D. Bernal
John Desmond Bernal FRS was one of Britain’s best known and most controversial scientists, called "Sage" by his friends, and known for pioneering X-ray crystallography in molecular biology.-Origin and education:His family was Irish, of mixed Italian and Spanish/Portuguese Sephardic Jewish origin...
's short-lived acceptance of the Langmuir-Wrinch hypothesis that protein folding
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
is driven by hydrophobic association. Nevertheless, cyclol bonds were identified in small, naturally occurring cyclic peptide
Cyclic peptide
Cyclic peptides are polypeptide chains whose amino and carboxyl termini are themselves linked together with a peptide bond that forms a circular chain. A number of cyclic peptides have been discovered in nature and they can range anywhere from just a few amino acids in length, to hundreds...
s in the 1950s.
Clarification of the modern terminology is appropriate. The classic cyclol reaction is the addition of the NH amine of a peptide group
Peptide bond
This article is about the peptide link found within biological molecules, such as proteins. A similar article for synthetic molecules is being created...
to the C=O carbonyl group of another; the resulting compound is now called an azacyclol. By analogy, an oxacyclol is formed when an OH hydroxyl group is added to a peptidyl carbonyl group. Likewise, a thiacyclol is formed by adding an SH thiol moiety to a peptidyl carbonyl group.
The oxacyclol alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
ergotamine from the fungus
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
Claviceps purpurea was the first identified cyclol. The cyclic depsipeptide serratamolide is also formed by an oxacyclol reaction. Chemically analogous cyclic thiacyclols have also been obtained. Classic azacyclols have been observed in small molecules and tripeptides. Peptides are naturally produced from the reversion of azacylols, a key prediction of the cyclol model. Hundreds of cyclol molecules have now been identified, despite Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
's calculation that such molecules should not exist because of their unfavorably high energy
Energy
In physics, energy is an indirectly observed quantity. It is often understood as the ability a physical system has to do work on other physical systems...
.
After a long hiatus during which she worked mainly on the mathematics of X-ray crystallography
X-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
, Wrinch responded to these discoveries with renewed enthusiasm for the cyclol model and its relevance in biochemistry. She also published two books describing the cyclol theory and small peptides in general.
Illustration of the scientific method
The cyclol model of protein structure is an example of empiricalEmpirical
The word empirical denotes information gained by means of observation or experimentation. Empirical data are data produced by an experiment or observation....
falsifiability
Falsifiability
Falsifiability or refutability of an assertion, hypothesis or theory is the logical possibility that it can be contradicted by an observation or the outcome of a physical experiment...
acting as part of the scientific method
Scientific method
Scientific method refers to a body of techniques for investigating phenomena, acquiring new knowledge, or correcting and integrating previous knowledge. To be termed scientific, a method of inquiry must be based on gathering empirical and measurable evidence subject to specific principles of...
. An original hypothesis
Hypothesis
A hypothesis is a proposed explanation for a phenomenon. The term derives from the Greek, ὑποτιθέναι – hypotithenai meaning "to put under" or "to suppose". For a hypothesis to be put forward as a scientific hypothesis, the scientific method requires that one can test it...
is made that accounts for unexplained experimental observations; the consequences of this hypothesis are worked out, leading to predictions that are tested by experiment. In this case, the key hypothesis was that the cyclol form of the peptide group could be favored over the amide form. This hypothesis led to the predictions of the cyclol-6 molecule and the cyclol fabric, which in turn suggested the model of semi-regular polyhedra for globular proteins. A key testable prediction was that a folded protein's carbonyl groups should be largely converted to hydroxyl groups; however, spectroscopic and chemical experiments showed that this prediction was incorrect. The cyclol model also predicts a high lateral density of amino acids in folded proteins and in films that does not agree with experiment. Hence, the cyclol model could be rejected and the search begun for new hypotheses of protein structure
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
, such as the models of the alpha helix
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
proposed in the 1940s and 1950s.
It is sometimes argued that the cyclol hypothesis should never have been advanced, because of its a priori flaws, e.g., its steric clashes, its inability to accommodate proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
, and the high free energy
Thermodynamic free energy
The thermodynamic free energy is the amount of work that a thermodynamic system can perform. The concept is useful in the thermodynamics of chemical or thermal processes in engineering and science. The free energy is the internal energy of a system less the amount of energy that cannot be used to...
disfavoring the cyclol reaction itself. Although such flaws rendered the cyclol hypothesis implausible, they did not make it impossible. The cyclol model was the first well-defined structure proposed for globular proteins, and too little was then known of intramolecular forces and protein structure to reject it immediately. It neatly explained several general properties of proteins and accounted for then-anomalous experimental observations. Although generally incorrect, some elements of the cyclol theory were eventually verified, such as the cyclol reactions and the role of hydrophobic interactions
Hydrophobe
In chemistry, hydrophobicity is the physical property of a molecule that is repelled from a mass of water....
in protein folding
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
. A useful comparison is the Bohr model
Bohr model
In atomic physics, the Bohr model, introduced by Niels Bohr in 1913, depicts the atom as a small, positively charged nucleus surrounded by electrons that travel in circular orbits around the nucleus—similar in structure to the solar system, but with electrostatic forces providing attraction,...
of the hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
atom
Atom
The atom is a basic unit of matter that consists of a dense central nucleus surrounded by a cloud of negatively charged electrons. The atomic nucleus contains a mix of positively charged protons and electrically neutral neutrons...
, which was considered implausible from its inception, even by its creator, yet led the way to the ultimately correct theory of quantum mechanics
Quantum mechanics
Quantum mechanics, also known as quantum physics or quantum theory, is a branch of physics providing a mathematical description of much of the dual particle-like and wave-like behavior and interactions of energy and matter. It departs from classical mechanics primarily at the atomic and subatomic...
. Similarly, Linus Pauling
Linus Pauling
Linus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
proposed a well-defined model of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
that was likewise implausible yet thought-provoking to other investigators. The cyclol story is an example of where an area of science progressed by formulating a well-defined hypothesis, testing it and eliminating it as incorrect.
Conversely, the cyclol model is an example of an incorrect scientific theory of great symmetry
Symmetry
Symmetry generally conveys two primary meanings. The first is an imprecise sense of harmonious or aesthetically pleasing proportionality and balance; such that it reflects beauty or perfection...
and beauty
Beauty
Beauty is a characteristic of a person, animal, place, object, or idea that provides a perceptual experience of pleasure, meaning, or satisfaction. Beauty is studied as part of aesthetics, sociology, social psychology, and culture...
, two qualities that can be regarded as signs of "obviously true" scientific theories. For example, the Watson
James D. Watson
James Dewey Watson is an American molecular biologist, geneticist, and zoologist, best known as one of the co-discoverers of the structure of DNA in 1953 with Francis Crick...
-Crick
Francis Crick
Francis Harry Compton Crick OM FRS was an English molecular biologist, biophysicist, and neuroscientist, and most noted for being one of two co-discoverers of the structure of the DNA molecule in 1953, together with James D. Watson...
double helix model of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
is sometimes said to be "obvious" because of its plausible hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
ing and symmetry; nevertheless, other, less symmetrical structures of DNA are favored under different conditions. Similarly, the beautiful theory of general relativity
General relativity
General relativity or the general theory of relativity is the geometric theory of gravitation published by Albert Einstein in 1916. It is the current description of gravitation in modern physics...
was considered by Albert Einstein
Albert Einstein
Albert Einstein was a German-born theoretical physicist who developed the theory of general relativity, effecting a revolution in physics. For this achievement, Einstein is often regarded as the father of modern physics and one of the most prolific intellects in human history...
as not needing experimental verification; yet even this theory will require revision for consistency with quantum field theory
Quantum field theory
Quantum field theory provides a theoretical framework for constructing quantum mechanical models of systems classically parametrized by an infinite number of dynamical degrees of freedom, that is, fields and many-body systems. It is the natural and quantitative language of particle physics and...
. The example of the cyclol model illustrates that all scientific theories, even the most beautiful and symmetrical, must be tested by experiment and that no theory is obviously true a priori, only more plausible.
See also
- Primary structurePrimary structureThe primary structure of peptides and proteins refers to the linear sequence of its amino acid structural units. The term "primary structure" was first coined by Linderstrøm-Lang in 1951...
- Peptide bondPeptide bondThis article is about the peptide link found within biological molecules, such as proteins. A similar article for synthetic molecules is being created...
- InsulinInsulinInsulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
- Denaturation (biochemistry)Denaturation (biochemistry)Denaturation is a process in which proteins or nucleic acids lose their tertiary structure and secondary structure by application of some external stress or compound, such as a strong acid or base, a concentrated inorganic salt, an organic solvent , or heat...
- Dorothy Maud WrinchDorothy Maud WrinchDorothy Maud Wrinch was a mathematician and biochemical theorist best known for her attempt to deduce protein structure using mathematical principles....
- Linus PaulingLinus PaulingLinus Carl Pauling was an American chemist, biochemist, peace activist, author, and educator. He was one of the most influential chemists in history and ranks among the most important scientists of the 20th century...
Further reading
- "Protein Units Put in Graphic 'Cage'," New York Times, 19 April 1940, page 14.
- "Waffle-Iron Theory of Proteins," New York Times, 2 February 1947, page E9.
- Structures of Matter and Patterns in Science, inspired by the work and life of Dorothy Wrinch, 1894–1976, Proceedings of a Symposium held at Smith CollegeSmith CollegeSmith College is a private, independent women's liberal arts college located in Northampton, Massachusetts. It is the largest member of the Seven Sisters...
, NorthamptonNorthampton, MassachusettsThe city of Northampton is the county seat of Hampshire County, Massachusetts, United States. As of the 2010 census, the population of Northampton's central neighborhoods, was 28,549...
, MassachusettsMassachusettsThe Commonwealth of Massachusetts is a state in the New England region of the northeastern United States of America. It is bordered by Rhode Island and Connecticut to the south, New York to the west, and Vermont and New Hampshire to the north; at its east lies the Atlantic Ocean. As of the 2010...
on 28–30 September 1977. - Selected papers of Dorothy WrinchDorothy Maud WrinchDorothy Maud Wrinch was a mathematician and biochemical theorist best known for her attempt to deduce protein structure using mathematical principles....
, from the Sophia SmithSophia SmithSophia Smith founded Smith College in 1870 with the substantial estate she inherited from her father and siblings....
Collection. Marjorie Senechal, editor. Schenkman Publishing Company, 1980.