Peng Yunhui, Yang Ye, Li Lin, Jia Zhe, Cao Weiguo, Alexov Emil
Computational Biophysics and Bioinformatics Lab, Department of Physics, Clemson University, Clemson, SC, United States.
Department of Genetics and Biochemistry, Clemson University, Clemson, SC, United States.
Front Mol Biosci. 2019 Sep 4;6:74. doi: 10.3389/fmolb.2019.00074. eCollection 2019.
Here we report a novel approach, the DelPhiForce Molecular Dynamics (DFMD) method, for steered molecular dynamics simulations to model receptor-ligand association involving charged species. The main purpose of developing DFMD is to simulate ligand's trajectory toward the receptor and thus to predict the "entrance" of the binding pocket and conformational changes associated with the binding. We demonstrate that the DFMD is superior compared with molecular dynamics simulations applying standard cut-offs, provides correct binding forces, allows for modeling the ligand approach at long distances and thus guides the ligand toward the correct binding spot, and it is very fast (frequently the binding is completed in <1 ns). The DFMD is applied to model the binding of two ligands to a receptor (spermine synthase) and it is demonstrated that it guides the ligands toward the corresponding pockets despite of the initial ligand's position with respect to the receptor. Predicted conformational changes and the order of ligand binding are experimentally verified.
在此，我们报告了一种新方法——德尔菲力分子动力学（DFMD）方法，用于进行引导分子动力学模拟，以对涉及带电物种的受体 - 配体结合进行建模。开发DFMD的主要目的是模拟配体朝向受体的轨迹，从而预测结合口袋的“入口”以及与结合相关的构象变化。我们证明，与应用标准截止值的分子动力学模拟相比，DFMD具有优越性，它能提供正确的结合力，允许在远距离对配体接近过程进行建模，从而引导配体到达正确的结合位点，并且速度非常快（通常结合在<1 ns内完成）。DFMD被应用于模拟两种配体与一种受体（精胺合酶）的结合，结果表明，无论配体相对于受体的初始位置如何，它都能引导配体到达相应的口袋。预测的构象变化和配体结合顺序得到了实验验证。
