Optimizing energy functions for protein-protein interface design

Journal of Computational Chemistry
Oz SharabiJulia M Shifman

Abstract

Protein design methods have been originally developed for the design of monomeric proteins. When applied to the more challenging task of protein–protein complex design, these methods yield suboptimal results. In particular, they often fail to recapitulate favorable hydrogen bonds and electrostatic interactions across the interface. In this work, we aim to improve the energy function of the protein design program ORBIT to better account for binding interactions between proteins. By using the advanced machine learning framework of conditional random fields, we optimize the relative importance of all the terms in the energy function, attempting to reproduce the native side-chain conformations in protein–protein interfaces. We evaluate the performance of several optimized energy functions, each describes the van der Waals interactions using a different potential. In comparison with the original energy function, our best energy function (a) incorporates a much “softer” repulsive van der Waals potential, suitable for the discrete rotameric representation of amino acid side chains; (b) does not penalize burial of polar atoms, reflecting the frequent occurrence of polar buried residues in protein–protein interfaces; and (c) significant...Continue Reading

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Citations

Sep 10, 2011·Bioinformatics·Iain H MoalPaul A Bates
Jan 5, 2014·IEEE/ACM Transactions on Computational Biology and Bioinformatics·Yao-Ming Huang, Christopher Bystroff
Sep 26, 2013·Biochemical Society Transactions·Oz SharabiJulia M Shifman
Jul 21, 2015·ELife·Anna Vangone, Alexandre Mjj Bonvin
Jul 23, 2013·Current Opinion in Structural Biology·Iain H MoalJuan Fernández-Recio
Oct 21, 2014·PloS One·Ariel ErijmanJulia M Shifman
Jun 25, 2016·Journal of Chemical Theory and Computation·Christopher M TophamIsabelle André
Jan 2, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jianfu ZhouGevorg Grigoryan
Oct 8, 2019·Bioinformatics·Xiaoqiang HuangYang Zhang

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