Computational prediction of protein–protein binding affinities

Till Siebenmorgen,Martin Zacharias

doi:10.1002/wcms.1448

Till Siebenmorgen, Martin Zacharias

Open Access

https://doi.org/10.1002/wcms.1448

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Abstract

AbstractProtein–protein interactions form central elements of almost all cellular processes. Knowledge of the structure of protein–protein complexes but also of the binding affinity is of major importance to understand the biological function of protein–protein interactions. Even weak transient protein–protein interactions can be of functional relevance for the cell during signal transduction or regulation of metabolism. The structure of a growing number of protein–protein complexes has been solved in recent years. Combined with docking approaches or template‐based methods, it is possible to generate structural models of many putative protein–protein complexes or to design new protein–protein interactions. In order to evaluate the functional relevance of putative or predicted protein–protein complexes, realistic binding affinity prediction is of increasing importance. Several computational tools ranging from simple force‐field or knowledge‐based scoring of single protein–protein complexes to ensemble‐based approaches and rigorous binding free energy simulations are available to predict relative and absolute binding affinities of complexes. With a focus on molecular mechanics force‐field approaches the present review aims at presenting an overview on available methods and discussing advantages, approximations, and limitations of the various methods.This article is categorized under: Molecular and Statistical Mechanics > Molecular Interactions Molecular and Statistical Mechanics > Free Energy Methods Software > Molecular Modeling

Highlights

The interaction of proteins is of fundamental importance for basically all processes in living systems
Interaction energies obtained from molecular mechanics (MM)-PBSA or MM-GBSA can show significant statistical errors due to numerically small interaction energies that need to be calculated from subtraction of numerically large and slowly converging mean energies
Judging if a predicted complex geometry or putative domain–domain interaction is stable and of functional relevance is of increasing importance

Summary

| INTRODUCTION

The interaction of proteins is of fundamental importance for basically all processes in living systems. Even in cases of significant average target–template similarity, the quality of the alignment is often not uniform along the whole protein sequence, for example, due to insertions or deletions in the aligned sequences which can result in structural inaccuracies Overlap of such inaccurate structural segments with the protein region in contact with binding partners may interfere with the possibility to produce near-native complexes using template-based modeling or rigid docking methods. 4 | MM-POISSON–BOLTZMANN/SURFACE AREA AND MM-GENERALIZED BORN/SURFACE AREA ENSEMBLE-BASED “ENDPOINT” FREE ENERGY

METHODS

Findings

| CONCLUSION