Pal Rajat Kumar, Haider Kamran, Kaur Divya, Flynn William, Xia Junchao, Levy Ronald M, Taran Tetiana, Wickstrom Lauren, Kurtzman Tom, Gallicchio Emilio
Department of Chemistry, Brooklyn College, 2900 Bedford Avenue, Brooklyn, New York, 11210, USA.
Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY, 10016, USA.
J Comput Aided Mol Des. 2017 Jan;31(1):29-44. doi: 10.1007/s10822-016-9956-6. Epub 2016 Sep 30.
As part of the SAMPL5 blinded experiment, we computed the absolute binding free energies of 22 host-guest complexes employing a novel approach based on the BEDAM single-decoupling alchemical free energy protocol with parallel replica exchange conformational sampling and the AGBNP2 implicit solvation model specifically customized to treat the effect of water displacement as modeled by the Hydration Site Analysis method with explicit solvation. Initial predictions were affected by the lack of treatment of ionic charge screening, which is very significant for these highly charged hosts, and resulted in poor relative ranking of negatively versus positively charged guests. Binding free energies obtained with Debye-Hückel treatment of salt effects were in good agreement with experimental measurements. Water displacement effects contributed favorably and very significantly to the observed binding affinities; without it, the modeling predictions would have grossly underestimated binding. The work validates the implicit/explicit solvation approach employed here and it shows that comprehensive physical models can be effective at predicting binding affinities of molecular complexes requiring accurate treatment of conformational dynamics and hydration.
作为SAMPL5盲法实验的一部分，我们采用了一种新颖的方法来计算22种主客体复合物的绝对结合自由能。该方法基于BEDAM单解耦炼金术自由能协议，采用并行副本交换构象采样，并使用专门定制的AGBNP2隐式溶剂化模型来处理水置换效应，水置换效应通过水化位点分析方法进行显式溶剂化建模。初始预测受到缺乏离子电荷筛选处理的影响，这对这些高电荷主体非常重要，并导致带负电与带正电客体的相对排序不佳。用德拜-休克尔处理盐效应得到的结合自由能与实验测量结果吻合良好。水置换效应有利于并非常显著地贡献了观察到的结合亲和力；没有它，建模预测将严重低估结合力。这项工作验证了这里采用的隐式/显式溶剂化方法，并且表明综合物理模型在预测需要精确处理构象动力学和水化的分子复合物的结合亲和力方面是有效的。
