Protein-Ligand Binding Free-Energy Calculations with ARROW─A Purely First-Principles Parameterized Polarizable Force Field.
Protein-Ligand Binding Free-Energy Calculations with ARROW─A Purely First-Principles Parameterized Polarizable Force Field.
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DOI：
10.1021/acs.jctc.2c00930
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发表时间：
2022-12-13
影响因子：
5.5
通讯作者：
Fain, Boris
中科院分区：
文献类型：
--
作者：
Nawrocki, Grzegorz;Leontyev, Igor;Sakipov, Serzhan;Darkhovskiy, Mikhail;Kurnikov, Igor;Pereyaslavets, Leonid;Kamath, Ganesh;Voronina, Ekaterina;Butin, Oleg;Illarionov, Alexey;Olevanov, Michael;Kostikov, Alexander;Ivahnenko, Ilya;Patel, Dhilon S.;Sankaranarayanan, Subramanian K. . R. S.;Kurnikova, Maria G.;Lock, Christopher;Crooks, Gavin E.;Levitt, Michael;Kornberg, Roger D.;Fain, Boris
基于分子动力学(MD)模拟的蛋白质-配体结合自由能计算已成为电子药物设计的有力工具。在这里，我们介绍了用箭力场(FF)获得的结果-一个多极可极化和基于物理的模型，所有参数完全适合高水平从头算量子力学(QM)计算。Arrow已经证明了它能够以前所未有的精度测定任意中性化合物的溶剂化自由能。ARROW FF参数化现已扩展到包括包括带电基团在内的所有氨基酸，允许对一系列蛋白质-配体系统进行分子模拟，并预测它们的相对结合自由能。我们通过应用一种新的技术来确保足够的采样，该技术基于哈密顿副本交换(HREX)与通过势软化和非平衡MD产生的构象库的耦合。Arrow为这里研究的三种蛋白质体系中的两种(∼和凝血酶)提供了接近化学精度的预测(平均绝对误差为0.5千卡/摩尔)。第三个蛋白质系统(CDK2)揭示了精确描述涉及极性和带电物种的二聚体相互作用能的困难。总体而言，对于这里研究的所有三个蛋白质系统，箭头FF预测了配体的相对结合自由能，其准确度与领先的不可极化力场相似。
Protein–ligand binding free-energy calculations using molecular dynamics (MD) simulations have emerged as a powerful tool for in silico drug design. Here, we present results obtained with the ARROW force field (FF)—a multipolar polarizable and physics-based model with all parameters fitted entirely to high-level ab initio quantum mechanical (QM) calculations. ARROW has already proven its ability to determine solvation free energy of arbitrary neutral compounds with unprecedented accuracy. The ARROW FF parameterization is now extended to include coverage of all amino acids including charged groups, allowing molecular simulations of a series of protein–ligand systems and prediction of their relative binding free energies. We ensure adequate sampling by applying a novel technique that is based on coupling the Hamiltonian Replica exchange (HREX) with a conformation reservoir generated via potential softening and nonequilibrium MD. ARROW provides predictions with near chemical accuracy (mean absolute error of ∼0.5 kcal/mol) for two of the three protein systems studied here (MCL1 and Thrombin). The third protein system (CDK2) reveals the difficulty in accurately describing dimer interaction energies involving polar and charged species. Overall, for all of the three protein systems studied here, ARROW FF predicts relative binding free energies of ligands with a similar accuracy level as leading nonpolarizable force fields.
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影响因子：
4.1
作者：
BENNETT, CH
通讯作者：
BENNETT, CH
影响因子：
4.1
作者：
He, Xibing;Liu, Shuhan;Wang, Junmei
通讯作者：
Wang, Junmei
影响因子：
56.9
作者：
BASH, PA;SINGH, UC;KOLLMAN, PA
通讯作者：
KOLLMAN, PA
影响因子：
5.5
作者：
Giese, Timothy J.;Panteva, Maria T.;Chen, Haoyuan;York, Darrin M.
通讯作者：
York, Darrin M.
影响因子：
3
作者：
Bernardi, Rafael C.;Melo, Marcelo C. R.;Schulten, Klaus
通讯作者：
Schulten, Klaus