Recognizing protein–protein interfaces with empirical potentials and reduced amino acid alphabets

BackgroundIn 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.ResultsPerformance 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.ConclusionThis 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.

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abstract: The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.

title: CHARMM: A program for macromolecular energy, minimization, and dynamics calculations
abstract: CHARMM (Chemistry at HARvard Macromolecular Mechanics) is a highly flexible computer program which uses empirical energy functions to model macromolecular systems. The program can read or model build structures, energy minimize them by first‐ or second‐derivative techniques, perform a normal mode or molecular dynamics simulation, and analyze the structural, equilibrium, and dynamic properties determined in these calculations. The operations that CHARMM can perform are described, and some implementation details are given. A set of parameters for the empirical energy function and a sample run are included.

title: Restart procedures for the conjugate gradient method
abstract: The conjugate gradient method is particularly useful for minimizing functions of very many variables because it does not require the storage of any matrices. However the rate of convergence of the algorithm is only linear unless the iterative procedure is “restarted” occasionally. At present it is usual to restart everyn or (n + 1) iterations, wheren is the number of variables, but it is known that the frequency of restarts should depend on the objective function. Therefore the main purpose of this paper is to provide an algorithm with a restart procedure that takes account of the objective function automatically. Another purpose is to study a multiplying factor that occurs in the definition of the search direction of each iteration. Various expressions for this factor have been proposed and often it does not matter which one is used. However now some reasons are given in favour of one of these expressions. Several numerical examples are reported in support of the conclusions of this paper.

title: Protein molecular dynamics with the generalized born/ACE solvent model
abstract: Implicit solvent models are increasingly important for the study of proteins in aqueous solution. Here, the generalized Born (GB) solvent polarization model as implemented in the analytical ACE potential [Schaefer and Karplus (1996)  is used to perform molecular dynamics simulations of two small, homologous proteins: the immunoglobulin‐binding domain of streptococcal protein G and the Ras binding domain of Raf. Several model parameterizations are compared through more than 60 ns of simulation. Results are compared with two simpler solvent models—an accessible surface area model and a distant‐dependent dielectric model, with finite‐difference Poisson calculations, with existing explicit solvent simulations, and with experimental data. The simpler models yield stable but distorted structures. The best GB/ACE implementation uses a set of atomic Voronoi volumes reported recently, obtained by averaging over a large database of crystallographic protein structures. A 20% reduction is applied to the volumes, compensating in an average sense for an excessive de‐screening of individual charges inherent in the ACE self‐energy and for an undersolvation of dipolar groups inherent in the GB screening function. This GB/ACE parameterization yields stable trajectories on the 0.5–1‐ns time scale that deviate moderately (∼1.5–2.5 Å) from the X‐ray structure, reproduce approximately the surface distribution of charged, polar, and hydrophobic groups, and reproduce accurately backbone flexibility as measured by amide NMR‐order parameters. Over longer time scales (1.5–3 ns), some of the protein G runs escape from the native energy basin and deviate strongly (3 Å) from the native structure. The conformations sampled during the transition out of the native energy basin are overstabilized by the GB/ACE solvation model, as compared with a numerical treatment of the full dielectric continuum model. Proteins 2001;45:144–158.