Flores-Canales Jose C, Kurnikova Maria
Department of Chemistry, Carnegie Mellon University , Pittsburgh, Pennsylvania 15213, United States.
J Chem Theory Comput. 2015 Jun 9;11(6):2550-9. doi: 10.1021/ct501090y.
Accelerated molecular dynamics (aMD) is a promising sampling method to generate an ensemble of conformations and to explore the free energy landscape of proteins in explicit solvent. Its success resides in its ability to reduce barriers in the dihedral and the total potential energy space. However, aMD simulations of large proteins can generate large fluctuations of the dihedral and total potential energy with little conformational changes in the protein structure. To facilitate wider conformational sampling of large proteins in explicit solvent, we developed a direct intrasolute electrostatic interactions accelerated MD (DISEI-aMD) approach. This method aims to reduce energy barriers within rapidly changing electrostatic interactions between solute atoms at short-range distances. It also results in improved reconstruction quality of the original statistical ensemble of the system. Recently, we characterized a pH-dependent partial unfolding of diphtheria toxin translocation domain (T-domain) using microsecond long MD simulations. In this work, we focus on the study of conformational changes of a low-pH T-domain model in explicit solvent using DISEI-aMD. On the basis of the simulations of the low-pH T-domain model, we show that the proposed sampling method accelerates conformational rearrangement significantly faster than multiple standard aMD simulations and microsecond long conventional MD simulations.
加速分子动力学（aMD）是一种很有前景的采样方法，可用于生成构象集合，并在显式溶剂中探索蛋白质的自由能景观。它的成功在于能够降低二面角和总势能空间中的势垒。然而，对大型蛋白质进行aMD模拟时，二面角和总势能可能会产生很大波动，而蛋白质结构的构象变化却很小。为了促进在显式溶剂中对大型蛋白质进行更广泛的构象采样，我们开发了一种溶质内直接静电相互作用加速MD（DISEI-aMD）方法。该方法旨在降低短程距离内溶质原子之间快速变化的静电相互作用中的能量势垒。它还能提高系统原始统计系综的重构质量。最近，我们使用微秒级长时间MD模拟表征了白喉毒素转位结构域（T结构域）的pH依赖性部分去折叠。在这项工作中，我们专注于使用DISEI-aMD研究显式溶剂中低pH值T结构域模型的构象变化。基于低pH值T结构域模型的模拟，我们表明，所提出的采样方法比多个标准aMD模拟和微秒级长时间传统MD模拟能显著更快地加速构象重排。
