Recognizing protein–protein interfaces with empirical potentials and reduced amino acid alphabets
Open Access
- 27 July 2007
- journal article
- Published by Springer Science and Business Media LLC in BMC Bioinformatics
- Vol. 8 (1), 270
- https://doi.org/10.1186/1471-2105-8-270
Abstract
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 ressources, 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.Keywords
This publication has 46 references indexed in Scilit:
- The Many Faces of Protein–Protein Interactions: A Compendium of Interface GeometryPLoS Computational Biology, 2006
- Hot Regions in Protein–Protein Interactions: The Organization and Contribution of Structurally Conserved Hot Spot ResiduesJournal of Molecular Biology, 2005
- Analysing Six Types of Protein–Protein InterfacesJournal of Molecular Biology, 2003
- Understanding hierarchical protein evolution from first principlesJournal of Molecular Biology, 2001
- The Protein Data BankNucleic Acids Research, 2000
- Stability of Designed Proteins against MutationsPhysical Review Letters, 1999
- Predicting protein stability changes upon mutation using database-derived potentials: solvent accessibility determines the importance of local versus non-local interactions along the sequenceJournal of Molecular Biology, 1997
- Enlarged representative set of protein structuresProtein Science, 1994
- Backbone-dependent Rotamer Library for Proteins Application to Side-chain PredictionJournal of Molecular Biology, 1993
- CHARMM: A program for macromolecular energy, minimization, and dynamics calculationsJournal of Computational Chemistry, 1983