Proteins: Docking, Simulations, Interactions

linked to PubMed where applicable.

Wodak S.J.

Docking and scoring protein complexes.

Proteins Structure Function &Bioinformatics. Sept.

The performance of methods for predicting protein-protein interactions at the atomic scale is assessed by evaluating blind predictions performed during 2005-2007 as part of Rounds 6-12 of the community-wide experiment on Critical Assessment of PRedicted Interactions (CAPRI). These Rounds also included a new scoring experiment, where a larger set of models contributed by the predictors was made available to groups developing scoring functions. These groups scored the uploaded set and submitted their own best models for assessment. The structures of nine protein complexes including one homodimer were used as targets. These targets represent biologically relevant interactions involved in gene expression, signal transduction, RNA, or protein processing and membrane maintenance. For all the targets except one, predictions started from the experimentally determined structures of the free (unbound) components or from models derived by homology, making it mandatory for docking methods to model the conformational changes that often accompany association. In total, 63 groups and eight automatic servers, a substantial increase from previous years, submitted docking predictions, of which 1994 were evaluated here. Fifteen groups submitted 305 models for five targets in the scoring experiment. Assessment of the predictions reveals that 31 different groups produced models of acceptable and medium accuracy-but only one high accuracy submission-for all the targets, except the homodimer. In the latter, none of the docking procedures reproduced the large conformational adjustment required for correct assembly, underscoring yet again that handling protein flexibility remains a major challenge. In the scoring experiment, a large fraction of the groups attained the set goal of singling out the correct association modes from incorrect solutions in the limited ensembles of contributed models. But in general they seemed unable to identify the best models, indicating that current scoring methods are probably not sensitive enough. With the increased focus on protein assemblies, in particular by structural genomics efforts, the growing community of CAPRI predictors is engaged more actively than ever in the development of better scoring functions and means of modeling conformational flexibility, which hold promise for much progress in the future. (c) 2007 Wiley-Liss, Inc.

Wodak S J.

From the Mediterranean coast to the shores of Lake Ontario Capri's premiere on the American continent.

Proteins Structure Function &Bioinformatics. Sept.

Launay G. Mendez R. Wodak S. J.. &Simonson T.

Recognizing protein-protein interfaces with empirical potentials and reduced amino acid alphabets.

BMC Bioinformatics 8 270.

BACKGROUND: In structural genomics, an important goal is the detection and classification of protein-protein interactions, given the structures of the interacting partners. We have developed empirical energy functions to identify native structures of protein-protein complexes among sets of decoy structures. To understand the role of amino acid diversity, we parameterized a series of functions, using a hierarchy of amino acid alphabets of increasing complexity, with 2, 3, 4, 6, and 20 amino acid groups. Compared to previous work, we used the simplest possible functional form, with residue-residue interactions and a stepwise distance-dependence. We used increased computational resources, however, constructing 290,000 decoys for 219 protein-protein complexes, with a realistic docking protocol where the protein partners are flexible and interact through a molecular mechanics energy function. The energy parameters were optimized to correctly assign as many native complexes as possible. To resolve the multiple minimum problem in parameter space, over 64000 starting parameter guesses were tried for each energy function. The optimized functions were tested by cross validation on subsets of our native and decoy structures, by blind tests on series of native and decoy structures available on the Web, and on models for 13 complexes submitted to the CAPRI structure prediction experiment. RESULTS: Performance is similar to several other statistical potentials of the same complexity. For example, the CAPRI target structure is correctly ranked ahead of 90% of its decoys in 6 cases out of 13. The hierarchy of amino acid alphabets leads to a coherent hierarchy of energy functions, with qualitatively similar parameters for similar amino acid types at all levels. Most remarkably, the performance with six amino acid classes is equivalent to that of the most detailed, 20-class energy function. CONCLUSION: This suggests that six carefully chosen amino acid classes are sufficient to encode specificity in protein-protein interactions, and provide a starting point to develop more complicated energy functions.

Janin J. & Wodak S.

The third CAPRI assessment meeting Toronto Canada April 20-21 2007.

Structure 15 755-9.

CAPRI is a community-wide experiment to test protein-protein docking methods in blind predictions. The Toronto meeting assessed structure predictions made from 2005-2007 on nine target protein-protein complexes or homodimers, and reported new developments in functions used to score predicted interactions, in treatment of conformational flexibility, and in taking nonstructural information into account in the predictions.

Mendez R. Leplae R. Lensink M.F. WodakS.J.

Assessment of CAPRI predictions in rounds 3-5shows progress in docking procedures.

Proteins. Aug 1;60(2): 150-69

The current status of docking procedures for predicting protein-protein interactions starting from their three-dimensional (3D) structure is reassessed by evaluating blind predictions, performed during 2003-2004 as part of Rounds 3-5 of the community-wide experiment on Critical Assessment of PRedicted Interactions (CAPRI). Ten newly determined structures of protein-protein complexes were used as targets for these rounds. They comprised 2 enzyme-inhibitor complexes, 2 antigen-antibody complexes, 2 complexes involved in cellular signaling, 2 homo-oligomers, and a complex between 2 components of the bacterial cellulosome. For most targets, the predictors were given the experimental structures of 1 unbound and 1 bound component, with the latter in a random orientation. For some, the structure of the free component was derived from that of a related protein, requiring the use of homology modeling. In some of the targets, significant differences in conformation were displayed between the bound and unbound components, representing a major challenge for the docking procedures. For 1 target, predictions could not go to completion. In total, 1866 predictions submitted by 30 groups were evaluated. Over one-third of these groups applied completely novel docking algorithms and scoring functions, with several of them specifically addressing the challenge of dealing with side-chain and backbone flexibility. The quality of the predicted interactions was evaluated by comparison to the experimental structures of the targets, made available for the evaluation, using the well-agreed-upon criteria used previously. Twenty-four groups, which for the first time included an automatic Web server, produced predictions ranking from acceptable to highly accurate for all targets, including those where the structures of the bound and unbound forms differed substantially. These results and a brief survey of the methods used by participants of CAPRI Rounds 3-5 suggest that genuine progress in the performance of docking methods is being achieved, with CAPRI acting as the catalyst.

Mendez R. and Wodak S.J.

Predictions of Protein-Protein Interactions: The CAPRI Experiment Its Evaluation and Implications.

Curr Opin Struct Biol. Apr 14(2): 242-249

Given the increasing interest in protein-protein interactions, the prediction of these interactions from sequence and structural information has become a booming activity. CAPRI, the community-wide experiment for assessing blind predictions of protein-protein interactions, is playing an important role in fostering progress in docking procedures. At the same time, novel methods are being derived for predicting regions of a protein that are likely to interact and for characterizing putative intermolecular contacts from sequence and structural data. Together with docking procedures, these methods provide an integrated computational approach that should be a valuable complement to genome-scale experimental studies of protein-protein interactions.

Janin J. Henrick K. Moult J. Sternberg M.J.Vajda S. Vakser I. and Wodak S.J.

CAPRI: Critical Assessment of Predicted Interactions.

Proteins Structure Function and Bioinformatics 52 2-9

CAPRI is a communitywide experiment to assess the capacity of protein-docking methods to predict protein-protein interactions. Nineteen groups participated in rounds 1 and 2 of CAPRI and submitted blind structure predictions for seven protein-protein complexes based on the known structure of the component proteins. The predictions were compared to the unpublished X-ray structures of the complexes. We describe here the motivations for launching CAPRI, the rules that we applied to select targets and run the experiment, and some conclusions that can already be drawn. The results stress the need for new scoring functions and for methods handling the conformation changes that were observed in some of the target systems. CAPRI has already been a powerful drive for the community of computational biologists who development docking algorithms. We hope that this issue of Proteins will also be of interest to the community of structural biologists, which we call upon to provide new targets for future rounds of CAPRI, and to all molecular biologists who view protein-protein recognition as an essential process. Copyright 2003 Wiley-Liss, Inc.

Mendez R. Laplae R. DeMaria L. and Wodak SJ.

Assessment of Blind Predictions of protein-Protein Interactions: Current Status of Docking Methods

Proteins Structure Function and Bioinformatics 52 51-67.

The current status of docking procedures for predicting protein-protein interactions starting from their three-dimensional structure is assessed from a first major evaluation of blind predictions. This evaluation was performed as part of a communitywide experiment on Critical Assessment of PRedicted Interactions (CAPRI). Seven newly determined structures of protein-protein complexes were available as targets for this experiment. These were the complexes between a kinase and its protein substrate, between a T-cell receptor beta-chain and a superantigen, and five antigen-antibody complexes. For each target, the predictors were given the experimental structures of the free components, or of one free and one bound component in a random orientation. The structure of the complex was revealed only at the time of the evaluation. A total of 465 predictions submitted by 19 groups were evaluated. These groups used a wide range of algorithms and scoring functions, some of which were completely novel. The quality of the predicted interactions was evaluated by comparing residue-residue contacts and interface residues to those in the X-ray structures and by analyzing the fit of the ligand molecules (the smaller of the two proteins in the complex) or of interface residues only, in the predicted versus target complexes. A total of 14 groups produced predictions, ranking from acceptable to highly accurate for five of the seven targets. The use of available biochemical and biological information, and in one instance structural information, played a key role in achieving this result. It was essential for identifying the native binding modes for the five correctly predicted targets, including the kinase-substrate complex where the enzyme changes conformation on association. But it was also the cause for missing the correct solution for the two remaining unpredicted targets, which involve unexpected antigen-antibody binding modes. Overall, this analysis reveals genuine progress in docking procedures but also illustrates the remaining serious limitations and points out the need for better scoring functions and more effective ways for handling conformational flexibility. Copyright 2003 Wiley-Liss, Inc.

Wodak S.J. & Janin J.

The structural basis of macromolecular recognition.

Advances in Protein Chemistry 61: 9-73.

Janin J. & Wodak S.J.

Protein modules and protein-protein interactions: towards a global view.

Advances in Protein Chemistry 61: 1-8

Janin J. and Wodak S.J.

The quaternary structure of Carbonmonoxy Hemoglobin Ypsilanti.

Proteins 15 1-4

We present a geometric analysis of the allosteric interface in the new Y state quaternary structure observed in liganded mutant hemoglobin Ypsilanti (beta 99 Asp-->Tyr) by Smith, F.R., Lattman, E.E., Carter, C.W., Jr. (Proteins 10: 81-91, 1991). The classical T to R quaternary structure change being a rotation of alpha beta dimers about an axis which is approximately parallel to the dimer axis of pseudosymmetry, the new quaternary structure is obtained by applying to R an additional rotation about an axis orthogonal to the first. This suggests that Y is a modified R state rather than an intermediate on the T to R pathway. Computer docking experiments designed to simulate the quaternary structure change support this suggestion.

Wodak S.J. De Crombrugghe M. and Janin J.

Computer studies of interactions betweenmacromolecules.

Prog.Biophys.Mol.Biol. 49 29-63.

Lesk A.M. Janin J. Wodak S.J. andChothia C.

Haemoglobin: the surface buried between thealpha 1 beta 1 and alpha 2 beta 2 dimers in the deoxy and oxystructures.

J.Mol.Biol. 183 267-270.

Using the newly available refined co-ordinates of deoxy and oxyhaemoglobin, we have re-examined and compared the interfaces between the dimers alpha 1 beta 1 and alpha 2 beta 2. The most extensive monomer-monomer contacts are between alpha 1 and beta 2, and, symmetrically, alpha 2 and beta 1. In oxyhaemoglobin these interfaces bury 700 A2 less protein surface than in deoxyhaemoglobin. The alpha 1 alpha 2 interface involves similar salt bridges in both forms, but in oxyhaemoglobin buries 240 A2 more surface than in deoxyhaemoglobin. There is a loosely packed beta 1 beta 2 interface burying 320 A2 of surface in oxyhaemoglobin; there is no beta 1 beta 2 interface in deoxyhaemoglobin. The greater stability of the deoxy form, in the absence of ligands, can be attributed to a combination of hydrophobic, van der Waals' and electrostatic interactions.

Janin J. and Wodak S.J.

Reaction pathway for the quaternary structure change in haemoglobin.

Biopolymers 24 509-526
Michel A. Durant F. and Wodak S.J.

Etude conformationnelle des complexes del'alpha-chymotrypsine.

Eur.J.Med.Chem.-Chim.Ther. 17 6 521-525.
Wodak S.J. and Janin J.

Preliminary analysis of the reaction pathway for the quaternary transition in hemoglobin using energy refinement and molecular graphics.

In Report of the CECAM Workshop onNon-bonded interactions and the specificity of protein association andfolding Brussels 47-64
Janin J. and Wodak S.J.

A docking algorithm applied to protein-protein association and to the allosteric mechanism of haemoglobin.

In Report of the CECAM Workshop onNon-bonded interactions and the specificity of protein association andfolding Brussels 5-46.
Wodak S.J.

Is it possible to deduce the interaction between two proteins from their 3-D structure?

In Molecular basis of mutant hemoglobin dysfunction P. Siegler (Ed.).Amsterdam Elsevier/North Holland 199-211.
Wodak S.J. and Janin J.

A computer analysis of protein-protein interaction.

Arch.Int.Physiol.Biochim. 86 473-474

Wodak S.J. and Janin J.

Computer analysis of protein-protein interaction.

J.Mol.Biol. 124 323-342