Institute for Molecular Modeling and Simulation, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria.
Institute for Molecular Modeling and Simulation, University of Natural Resources and Life Sciences (BOKU), Vienna, Austria.
Curr Opin Struct Biol. 2020 Apr;61:207-212. doi: 10.1016/j.sbi.2020.01.016. Epub 2020 Feb 20.
In recent years, calculations of binding affinities from molecular simulations seem to have matured significantly. While the number of applications of such methods in drug design and biotechnology increases, the number of truly new methodological developments decreases. This review provides an overview of the current status of the field as reflected in recent publications. The focus is on the challenges that remain when using endstate, alchemical and pathway methods. For endstate methods this is the calculation of entropic contributions. For alchemical methods there are unsolved problems associated with the solvation of the active site, sampling slow degrees of freedom and when modifying the net charge. For pathway methods achieving sufficient sampling remains challenging. New trends are also highlighted, including the use of pathway methods for the quantification of protein-protein interactions.
近年来，从分子模拟计算得到的结合亲和力似乎已经有了显著的进步。随着这些方法在药物设计和生物技术中的应用越来越多，真正的新方法发展却在减少。本综述概述了当前该领域的最新出版物所反映的现状。重点关注在使用终点法、变分法和路径法时仍然存在的挑战。对于终点法，这涉及到熵贡献的计算。对于变分法，仍然存在与活性位点溶剂化、采样慢自由度以及修改净电荷相关的未解决问题。对于路径法，实现足够的采样仍然具有挑战性。还强调了新的趋势，包括使用路径法来量化蛋白质-蛋白质相互作用。
