Ben-Shalom Ido Y, Lin Zhixiong, Radak Brian K, Lin Charles, Sherman Woody, Gilson Michael K
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 92093 La Jolla, California, United States.
Silicon Therapeutics LLC, Boston, Massachusetts 02110, United States.
J Chem Theory Comput. 2020 Dec 8;16(12):7883-7894. doi: 10.1021/acs.jctc.0c00785. Epub 2020 Nov 18.
Rigorous binding free energy methods in drug discovery are growing in popularity because of a combination of methodological advances, improvements in computer hardware, and workflow automation. These calculations typically use molecular dynamics (MD) to sample from the Boltzmann distribution of conformational states. However, when part or all of the binding sites is inaccessible to the bulk solvent, the time needed for water molecules to equilibrate between bulk solvent and the binding site can be well beyond what is practical with standard MD. This sampling limitation is problematic in relative binding free energy calculations, which compute the reversible work of converting ligand 1 to ligand 2 within the binding site. Thus, if ligand 1 is smaller and/or more polar than ligand 2, the perturbation may allow additional water molecules to occupy a region of the binding site. However, this change in hydration may not be captured by standard MD simulations and may therefore lead to errors in the computed free energy. We recently developed a hybrid Monte Carlo/MD (MC/MD) method, which speeds up the equilibration of water between bulk solvent and buried cavities, while sampling from the intended distribution of states. Here, we report on the use of this approach in the context of alchemical binding free energy calculations. We find that using MC/MD markedly improves the accuracy of the calculations and also reduces hysteresis between the forward and reverse perturbations, relative to matched calculations using only MD with or without the crystallographic water molecules. The present method is available for use in AMBER simulation software.
由于方法学的进步、计算机硬件的改进以及工作流程自动化等因素的综合作用，药物发现中严格的结合自由能方法越来越受欢迎。这些计算通常使用分子动力学（MD）从构象状态的玻尔兹曼分布中进行采样。然而，当部分或全部结合位点对本体溶剂不可达时，水分子在本体溶剂和结合位点之间达到平衡所需的时间可能远远超出标准MD的实际操作范围。这种采样限制在相对结合自由能计算中是个问题，相对结合自由能计算是计算在结合位点内将配体1转化为配体2的可逆功。因此，如果配体1比配体2更小和/或更具极性，这种扰动可能会使额外的水分子占据结合位点的一个区域。然而，这种水合作用的变化可能无法被标准MD模拟捕捉到，因此可能导致计算自由能出现误差。我们最近开发了一种混合蒙特卡罗/分子动力学（MC/MD）方法，该方法加快了本体溶剂和埋藏腔之间水的平衡，同时从预期的状态分布中进行采样。在此，我们报告这种方法在炼金术结合自由能计算中的应用。我们发现，与仅使用MD（有或没有结晶水分子）的匹配计算相比，使用MC/MD显著提高了计算的准确性，并且还减少了正向和反向扰动之间的滞后现象。本方法可用于AMBER模拟软件。
