力场极化对蛋白质相关运动的影响
Impact of Force Field Polarization on Correlated Motions of Proteins
AI总结：
本研究对比非极化CHARMM 36m加和力场与可极化Drude-2019力场对泛素和PPAR___蛋白相关运动的影响，发现后者RMS波动更大、相关运动更弱、天然接触丢失更多，首次量化了极化力场对该类研究的影响。
摘要：
蛋白质的相关运动是底物结合、信号转导、酶活性及别构效应等诸多生理机制的基础。这类运动源于生物分子的低频集体运动，目前大多通过分子动力学模拟开展研究。本文探究了分子动力学模拟中两种常用经验能量力场对相关运动的影响，分别是非极化的CHARMM 36m加和力场与可极化的Drude-2019力场。本研究以两种蛋白质为对象：泛素（一种动力学特征已被充分阐明的小蛋白）以及核受体蛋白PPAR___。PPAR___的配体结合域是研究重点，其功能是通过结合配体与共调节蛋白来调控转录，此前已有研究表明，一个相关运动的动力学网络可保障PPAR___配体结合相关信息的传递。我们开展了经典MD模拟，并从残基波动、残基相关图谱、群落网络分析及疏水簇分析四个维度对结果进行解析。研究发现，与非极化全原子加和力场相比，使用Drude-2019力场时RMS波动幅度更大，相关运动强度更低。对两种蛋白质中大型疏水簇的分析显示，采用Drude-2019力场的模拟中，天然接触的丢失程度高于全原子加和力场的模拟结果。本研究结果首次量化了可极化力场在聚焦相关运动的计算研究中产生的影响。
英文摘要：
Correlated motions of proteins underpin many physiological mechanisms, such as substrate binding, signal transduction, enzymatic activity and allostery. These motions arise from low frequency collective movements of biomolecules and have mostly been studied using molecular dynamics simulations. Here, we present the effects of two different empirical energy force fields used for molecular dynamics simulations on correlated motions -- the non-polarizable CHARMM 36m additive force field and the polarizable Drude-2019 force field. The study was conducted on two proteins, ubiquitin - a small protein with a well-described dynamic - and the nuclear receptor protein PPAR___. The ligand binding domain of PPAR___ was of particular interest since its function is to regulate transcription through ligand and coregulator protein binding. It has been previously shown that a dynamical network of correlated motions ensures the transmission of information related to PPAR___ ligand binding. We present the results of classical MD simulations where we analyze the results in terms of residue fluctuations, residue correlation maps, community network analysis and hydrophobic cluster analysis. We find that RMS fluctuations tend to be greater and correlated motions are less intense with Drude-2019 force field than with the non-polarizable all atom additive force field. Analysis of large hydrophobic clusters in the respective proteins show a greater loss of native contacts in the simulations using the Drude-2019 force field than in the simulations using the all atom force additive force field. Our results provide the first quantification of the impact of using a polarizable force field in computational studies that focus on correlated motions.
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