Binding Energy Distribution Analysis Method: Hamiltonian Replica Exchange with Torsional Flattening for Binding Mode Prediction and Binding Free Energy Estimation.
Binding Energy Distribution Analysis Method: Hamiltonian Replica Exchange with Torsional Flattening for Binding Mode Prediction and Binding Free Energy Estimation.
复制标题
结合能分布分析方法：用于结合模式预测和结合自由能估计的哈密顿复制品交换和扭转扁平化。
DOI：
10.1021/acs.jctc.6b00134
复制
发表时间：
2016
影响因子：
5.5
通讯作者：
Levy,RonaldM
中科院分区：
文献类型：
--
作者：
Mentes,Ahmet;Deng,Nan-Jie;Vijayan,RSK;Xia,Junchao;Gallicchio,Emilio;Levy,RonaldM
复杂生物系统的分子动力学建模受到模拟时间的限制。模拟常常陷入被高能屏障隔开的局部能量极小值附近。这里，我们在结合能量分布分析方法(BEDAM)中引入扭转平坦的哈密顿复制交换(H-REMD)，以减少扭转自由度上的能垒，并加快与蛋白质-配体结合相关的分子内自由度的采样。该方法在标准基准(T4溶菌酶/L99A/对二甲苯复合体)和来自SAMPL4盲挑战的HIV-1整合酶复合体文库上进行了测试。我们将扭转扁平策略应用于HIV整合酶LEDGF位点的53个已知结合子中的26个，发现有一个结合能景观朝向晶体结构。我们表明，当我们的方法从不正确的配体二面角构象的对接姿势开始时，我们的方法比原始方法在没有平坦化的情况下更有效地采样构象空间。在这些不利的情况下，可以在哈密顿复制交换模拟的几纳秒内从晶体姿势收敛到结合姿势。我们发现，在捕获是由于扭转能量以外的因素的情况下，扭转压平是不够的，例如形成错误的分子内氢键和堆积。目前正在努力推广处理这些案件的办法，从而使其更广泛地适用。
Molecular dynamics modeling of complex biological systems is limited by finite simulation time. The simulations are often trapped close to local energy minima separated by high energy barriers. Here, we introduce Hamiltonian replica exchange (H-REMD) with torsional flattening in the Binding Energy Distribution Analysis Method (BEDAM), to reduce energy barriers along torsional degrees of freedom and accelerate sampling of intramolecular degrees of freedom relevant to protein–ligand binding. The method is tested on a standard benchmark (T4 Lysozyme/L99A/p-xylene complex) and on a library of HIV-1 integrase complexes derived from the SAMPL4 blind challenge. We applied the torsional flattening strategy to 26 of the 53 known binders to the HIV Integrase LEDGF site found to have a binding energy landscape funneled toward the crystal structure. We show that our approach samples the conformational space more efficiently than the original method without flattening when starting from a poorly docked pose with incorrect ligand dihedral angle conformations. In these unfavorable cases convergence to a binding pose within 2–3 Å from the crystallographic pose is obtained within a few nanoseconds of the Hamiltonian replica exchange simulation. We found that torsional flattening is insufficient in cases where trapping is due to factors other than torsional energy, such as the formation of incorrect intramolecular hydrogen bonds and stacking. Work is in progress to generalize the approach to handle these cases and thereby make it more widely applicable.