CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
J Chem Theory Comput. 2021 Jan 12;17(1):13-28. doi: 10.1021/acs.jctc.0c00592. Epub 2020 Dec 22.
Understanding conformational change at an atomic level is significant when determining a protein functional mechanism. Replica exchange molecular dynamics (REMD) is a widely used enhanced sampling method to explore protein conformational space. However, REMD with an explicit solvent model requires huge computational resources, immensely limiting its application. In this study, a variation of parallel tempering metadynamics (PTMetaD) with the omission of solvent-solvent interactions in exchange attempts and the use of low-frequency modes calculated by normal-mode analysis (NMA) as collective variables (CVs), namely ossPTMetaD, is proposed with the aim to accelerate MD simulations simultaneously in temperature and geometrical spaces. For testing the performance of ossPTMetaD, five protein systems with diverse biological functions and motion patterns were selected, including large-scale domain motion (AdK), flap movement (HIV-1 protease and BACE1), and DFG-motif flip in kinases (p38α and c-Abl). The simulation results showed that ossPTMetaD requires much fewer numbers of replicas than temperature REMD (T-REMD) with a reduction of ∼70% to achieve a similar exchange ratio. Although it does not obey the detailed balance condition, ossPTMetaD provides consistent results with T-REMD and experimental data. The high accessibility of the large conformational change of protein systems by ossPTMetaD, especially in simulating the very challenging DFG-motif flip of protein kinases, demonstrated its high efficiency and robustness in the characterization of the large-scale protein conformational change pathway and associated free energy profile.
在确定蛋白质功能机制时，了解原子水平的构象变化是非常重要的。 replica exchange 分子动力学（REMD）是一种广泛使用的增强采样方法，用于探索蛋白质构象空间。然而，带有显式溶剂模型的 REMD 需要巨大的计算资源，极大地限制了它的应用。在这项研究中，提出了一种带有溶剂-溶剂相互作用省略的并行温度元动力学（PTMetaD）的变体，以及使用由正常模式分析（NMA）计算的低频模式作为集体变量（CVs），即 ossPTMetaD，旨在同时在温度和几何空间中加速 MD 模拟。为了测试 ossPTMetaD 的性能，选择了五个具有不同生物学功能和运动模式的蛋白质系统进行测试，包括大规模结构域运动（AdK）、瓣运动（HIV-1 蛋白酶和 BACE1）以及激酶中的 DFG-motif 翻转（p38α 和 c-Abl）。模拟结果表明，ossPTMetaD 需要比温度 REMD（T-REMD）少得多的副本数，副本数减少了约 70%，即可达到相似的交换率。尽管它不遵守详细平衡条件，但 ossPTMetaD 与 T-REMD 和实验数据提供了一致的结果。ossPTMetaD 使蛋白质系统的大构象变化具有很高的可及性，特别是在模拟蛋白激酶非常具有挑战性的 DFG-motif 翻转时，证明了其在大蛋白质构象变化途径和相关自由能分布的特征化方面的高效性和稳健性。
