Andrej Šali
Encyclopedia
Andrej Šali is a computational structural biologist
. He joined the faculty of the Rockefeller University
in 1995, following his postdoctoral research at Harvard University
. Since 2003, he has been the Professor and Vice Chair of the Department of Bioengineering and Therapeutic Sciences as well as the Scientific Director of California Institute for Quantitative Biosciences at University of California, San Francisco
. He also serves as an editor for the journal Structure
.
, 1987; his Ph.D. in Molecular Biophysics
from Birkbeck College
, University of London
, 1991 (working with Tom Blundell
); and did postdoctoral work at Harvard University
(working with Martin Karplus
).
and evolution
to study the structure
and function
of proteins. For example, he developed comparative protein structure modeling
by satisfaction of spatial restraints, implemented in the program MODELLER
and integrative structure determination of macromolecular assemblies, implemented in the program IMP.
In July 2006, the magazine Business 2.0
ranked Šali and Stephen Maurer together at 41st place among "50 Who Matter Now".
. The average citation per item is 80.60 and the number of times cited is 19,585. Also, the average citation per year is 851.52. Šali has a Hirsch-index
of 65, meaning 65 published items having at least 65 citations.
, which was written by Baker, the co-author of this article.
The objective of this algorithm is to generate many restraints on the structure of the target sequence, using its alignment to template structures as a guide. This is based on the assumption that corresponding distances and angles between two pairs of aligned residues in the target and template structures are similar. These homology-derived restraints are usually supplemented by stereochemical restraints on bond lenths, bond angles, dihedral angles, and nonbonded atom-atom contacts obtained from a molecular mechanics force field. This is known as analytical supplementation. Restraints derived from experimental data, such as those found in a structure database of protein families, can act as empirical supplementation. The extraction of spatial restraints from such a database is shown in Figure 2.
Each spatial restraint can be expressed as a conditional probability density function (pdf)
obtained by smoothing a histogram of restraint frequencies. In Figure 1 for example, given that residues Q...T in the template align with residues W...D in the target, the Cα-Cα homology-derived restraint can be supplemented with Cα-Cα distance data of W and D from the database on the condition that they align with Q and T respectively [p((Cα(W)-Cα(D))/(Cα(Q)-Cα(T)...))]. Consequently, a frequency histogram of Cα(W)-Cα(D) restraints is obtained and can be used for satifaction of the corresponding homology-derived spatial restraints.
In the final step of the algorithm, optimization is used to minimize violations of all the spatial restraints. This starts off by constructing a model using the distance and angle restraints on the target sequence derived from its alignment with template 3-Dimensional (3D) structures. Then, local restraints for residues close in proximity are satisfied by the method of conjugate gradients, introducing more longer-ranged restraints iteratively. The resulting model is refined with Molecular Dynamics (MD) using simulated annealing. This whole process is shown in Figure 3.
, protein sequence determines protein structure and this in turn determines protein function. Thus, comparative models allow for functional studies and annotation of proteins by fold recognition.
Research that have been carried out based on comparative models include:
Comparative modeling with MODELLER was also adpated in 3D-Jury, a meta-predictor of protein structures.
Biologist
A biologist is a scientist devoted to and producing results in biology through the study of life. Typically biologists study organisms and their relationship to their environment. Biologists involved in basic research attempt to discover underlying mechanisms that govern how organisms work...
. He joined the faculty of the Rockefeller University
Rockefeller University
The Rockefeller University is a private university offering postgraduate and postdoctoral education. It has a strong concentration in the biological sciences. It is also known for producing numerous Nobel laureates...
in 1995, following his postdoctoral research at Harvard University
Harvard University
Harvard University is a private Ivy League university located in Cambridge, Massachusetts, United States, established in 1636 by the Massachusetts legislature. Harvard is the oldest institution of higher learning in the United States and the first corporation chartered in the country...
. Since 2003, he has been the Professor and Vice Chair of the Department of Bioengineering and Therapeutic Sciences as well as the Scientific Director of California Institute for Quantitative Biosciences at University of California, San Francisco
University of California, San Francisco
The University of California, San Francisco is one of the world's leading centers of health sciences research, patient care, and education. UCSF's medical, pharmacy, dentistry, nursing, and graduate schools are among the top health science professional schools in the world...
. He also serves as an editor for the journal Structure
Structure (journal)
Structure is a peer-reviewed scientific journal founded by Wayne A. Hendrickson, Carl-Ivar Brändén and Alan R. Fersht in September 1993. It focuses on protein structure and related issues....
.
Education
Šali received his B.Sc. in Chemistry from the University of LjubljanaUniversity of Ljubljana
The University of Ljubljana is the oldest and largest university in Slovenia. With 64,000 enrolled graduate and postgraduate students, it is among the largest universities in Europe.-Beginnings:...
, 1987; his Ph.D. in Molecular Biophysics
Molecular biophysics
Molecular biophysics is a rapidly evolving interdisciplinary area of research that combines concepts in physics, chemistry, engineering, mathematics and biology...
from Birkbeck College
Birkbeck, University of London
Birkbeck, University of London is a public research university located in London, United Kingdom and a constituent college of the federal University of London. It offers many Master's and Bachelor's degree programmes that can be studied either part-time or full-time, though nearly all teaching is...
, University of London
University of London
-20th century:Shortly after 6 Burlington Gardens was vacated, the University went through a period of rapid expansion. Bedford College, Royal Holloway and the London School of Economics all joined in 1900, Regent's Park College, which had affiliated in 1841 became an official divinity school of the...
, 1991 (working with Tom Blundell
Tom Blundell
Sir Tom Leon Blundell, FRS, FMedSci is a British biochemist and science administrator. Up until 2009, he was the Sir William Dunn Professor of Biochemistry and head of the Department of Biochemistry at the University of Cambridge....
); and did postdoctoral work at Harvard University
Harvard University
Harvard University is a private Ivy League university located in Cambridge, Massachusetts, United States, established in 1636 by the Massachusetts legislature. Harvard is the oldest institution of higher learning in the United States and the first corporation chartered in the country...
(working with Martin Karplus
Martin Karplus
Martin Karplus is an Austrian-born American theoretical chemist. He has been Theodore William Richards Professor of Chemistry at Harvard University since 1979...
).
Work
He is using computation grounded in the laws of physicsPhysics
Physics is a natural science that involves the study of matter and its motion through spacetime, along with related concepts such as energy and force. More broadly, it is the general analysis of nature, conducted in order to understand how the universe behaves.Physics is one of the oldest academic...
and evolution
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
to study the 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...
and function
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...
of proteins. For example, he developed comparative protein structure modeling
Homology modeling
Homology modeling, also known as comparative modeling of protein refers to constructing an atomic-resolution model of the "target" protein from its amino acid sequence and an experimental three-dimensional structure of a related homologous protein...
by satisfaction of spatial restraints, implemented in the program MODELLER
MODELLER
MODELLER is a computer program used in producing homology models of protein tertiary structures as well as quaternary structures . It implements a technique inspired by nuclear magnetic resonance known as satisfaction of spatial restraints, by which a set of geometrical criteria are used to create...
and integrative structure determination of macromolecular assemblies, implemented in the program IMP.
In July 2006, the magazine Business 2.0
Business 2.0
Business 2.0 was a monthly magazine publication founded by magazine entrepreneur Chris Anderson, Mark Gross, and journalist James Daly in order to chronicle the rise of the "New Economy"...
ranked Šali and Stephen Maurer together at 41st place among "50 Who Matter Now".
Personal life
Šali is married to soprano (and former scientist) Heidi Moss and they have two daughters, Ava and Hana.Citation Analysis
As at 11 August 2011, Šali has a total of 279 publications, 243 of which are found on the Web of ScienceWeb of Science
ISI Web of Knowledge is an academic citation indexing and search service, which is combined with web linking and provided by Thomson Reuters. Web of Knowledge coverage encompasses the sciences, social sciences, arts and humanities. It provides bibliographic content and the tools to access, analyze,...
. The average citation per item is 80.60 and the number of times cited is 19,585. Also, the average citation per year is 851.52. Šali has a Hirsch-index
H-index
The h-index is an index that attempts to measure both the productivity and impact of the published work of a scientist or scholar. The index is based on the set of the scientist's most cited papers and the number of citations that they have received in other publications...
of 65, meaning 65 published items having at least 65 citations.
The Top Five Research Articles by Citation
| Number of Citations | Average Citation per Year | Title | Authors | Journal | Publication Year |
|---|---|---|---|---|---|
| 3980 | 209.68 | Comparative Protein Modeling by Satisfaction of Spatial Restraints | Sali A, Blundell TL | Journal of Molecular Biology | 1993 |
| 684 | 38.00 | How does a protein fold? | Sali A, Shakhnovich E, Karplus M | Nature | 1994 |
| 676 | 56.42 | Comparative Protein Structure Modeling of Genes and Genomes | Marti-Renom MA, Stuart AC, Fiser A, Sanchez R, Melo F, Sali A | Annual Review of Biophysics and Biomolecular Structure | 2000 |
| 641 | 58.27 | Protein Structure Prediction and Structural Genomics | Baker D, Sali A | Science | 2001 |
| 555 | 46.33 | Modeling of Loops in Protein Structures | Fiser A, Do RKG, Sali A | Protein Science | 2000 |
How does a protein fold?
In this article, proteins were shown to fold from a denatured state to its native conformation in three steps. This process starts off with a rapid collapse of a denatured state (out of 1016 possible states) randomly into one of 1010 possible semi-compact molten globules. Thereafter, a slow search for a transition state (out of 103 possible states) occurs. The protein consequently adopts its stable native fold in a fast final step.Comparative Protein Structure Modeling of Genes and Genomes
This is a review article on the steps in comparative protein structure modeling and how to perform evaluation to pick out errors in comparative models. The applications of such an endeavour are introduced and extension to whole genome (proteome) modeling is also discussed.Protein Structure Prediction and Structural Genomics
This review article is somewhat similar to Comparative Protein Structure Modeling of Genes and Genomes in that it also discusses about comparative modeling, with the inclusion of de novo modeling as an alternative for target proteins without a suitable template. An example of a program that does de novo (or ab initio) protein structure prediction is RosettaRosetta@home
Rosetta@home is a distributed computing project for protein structure prediction on the Berkeley Open Infrastructure for Network Computing platform, run by the Baker laboratory at the University of Washington...
, which was written by Baker, the co-author of this article.
Modeling of Loops in Protein Structures
A shortcoming of comparative modeling is that homologous protein sequences often have variable loop regions which cannot be accurately modeled. Thus sampling and optimization are used to model loop conformations.Most Important Algorithmic Contribution
Šali’s most important algorithmic contribution is the satisfaction of spatial restraints, which is used in his comparative protein structure modeling program called MODELLER. The algorithm is outlined in Figure 1.The objective of this algorithm is to generate many restraints on the structure of the target sequence, using its alignment to template structures as a guide. This is based on the assumption that corresponding distances and angles between two pairs of aligned residues in the target and template structures are similar. These homology-derived restraints are usually supplemented by stereochemical restraints on bond lenths, bond angles, dihedral angles, and nonbonded atom-atom contacts obtained from a molecular mechanics force field. This is known as analytical supplementation. Restraints derived from experimental data, such as those found in a structure database of protein families, can act as empirical supplementation. The extraction of spatial restraints from such a database is shown in Figure 2.
Each spatial restraint can be expressed as a conditional probability density function (pdf)
obtained by smoothing a histogram of restraint frequencies. In Figure 1 for example, given that residues Q...T in the template align with residues W...D in the target, the Cα-Cα homology-derived restraint can be supplemented with Cα-Cα distance data of W and D from the database on the condition that they align with Q and T respectively [p((Cα(W)-Cα(D))/(Cα(Q)-Cα(T)...))]. Consequently, a frequency histogram of Cα(W)-Cα(D) restraints is obtained and can be used for satifaction of the corresponding homology-derived spatial restraints.
In the final step of the algorithm, optimization is used to minimize violations of all the spatial restraints. This starts off by constructing a model using the distance and angle restraints on the target sequence derived from its alignment with template 3-Dimensional (3D) structures. Then, local restraints for residues close in proximity are satisfied by the method of conjugate gradients, introducing more longer-ranged restraints iteratively. The resulting model is refined with Molecular Dynamics (MD) using simulated annealing. This whole process is shown in Figure 3.
Research Impact
MODELLER has enabled proteins without a known crystal structure to be more accurately modeled than other comparative modeling programs. This is due to the incorporation of experimental data as spatial restraints imposed onto the target sequence. According to LeskArthur M. Lesk
Arthur M. Lesk, is an accomplished protein science researcher, who is currently a professor of biochemistry and molecular biology at the Pennsylvania State University, University Park.- Profile :...
, protein sequence determines protein structure and this in turn determines protein function. Thus, comparative models allow for functional studies and annotation of proteins by fold recognition.
Research that have been carried out based on comparative models include:
- Molecular replacementMolecular replacementMolecular replacement is a method of solving the phase problem in X-ray crystallography. MR relies upon the existence of a previously solved protein structure which is homologous to our unknown structure from which the diffraction data is derived.The first goal of the crystallographer is to...
in X-ray crystallographyX-ray crystallographyX-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... - Effect of Single-Nucleotide Polymorphisms on human diseases
Comparative modeling with MODELLER was also adpated in 3D-Jury, a meta-predictor of protein structures.
Some Notable Alumni from Šali Lab
| Name | Lab Position | Duration | Current Location | Current Position |
|---|---|---|---|---|
| Andras Fiser | Postdoctoral Fellow | Sep 1997 to Dec 2002 | Albert Einstein College of Medicine, Bronx, NY | Associate Professor |
| Marc A. Marti-Renom | Adjunct Assistant Professor | Feb 1999 to Jun 2006 | Principe Felipe Research Center, Valencia, Spain | Assistant Professor |
| M.S. Madhusudhan | Postdoctoral Scholar | Feb 2000 to Mar 2008 | Bioinformatics Institute, Singapore | Principal Investigator |
| David Barkan | Ph.D. Student | Sept 2006 to Oct 2011 | Protagonist Therapeutics | Staff Scientist |
Andras Fiser
- Number of Publications: 76
- Average Citation per Item: 41.45
- Number of Times Cited: 3150
- Average Citation per Year: 165.79
- H-index: 22
Marc A. Marti-Renom
- Number of Publications: 56
- Average Citation per Item: 45.25
- Number of Times Cited: 2534
- Average Citation per Year: 194.92
- H-index: 19
M.S. Madhusudhan
- Number of Publications: 35
- Average Citation per Item: 32.14
- Number of Times Cited: 1125
- Average Citation per Year: 86.54
- H-index: 15