在炼金术结合自由能预测中驯服多个结合位置：$β$ -环糊精主客体SAMPL9盲法挑战
Taming Multiple Binding Poses in Alchemical Binding Free Energy Prediction: the $β$-cyclodextrin Host-Guest SAMPL9 Blinded Challenge
摘要：
我们应用炼金术转移方法（ATM）和一个定制的固定部分电荷力场的SAMPL 9 BCD主客体结合自由能预测的挑战，包括五个吩噻嗪客人和两个环糊精主机之间形成的复合物的组合。多种化学形式，竞争性的结合姿势，和计算建模的挑战构成了重大障碍，获得可靠的计算预测这些系统。吩噻嗪客体在溶液中以通过氮转化相关的对映异构体的外消旋混合物的形式存在，所述氮转化以各种结合姿势结合宿主，每种结合姿势都需要单独的自由能分析。由于大尺寸的客人和主机的构象重组，这阻止了直接的绝对结合自由能的路线，结合自由能是通过一系列的绝对和相对结合炼金术步骤，为每个化学物种在每个绑定姿势。代谢加速构象采样被认为是必要的，以解决一些数值估计的收敛性差的构象捕获的影响。尽管存在这些挑战，我们的盲法预测定量地再现了$β$ -环糊精主体的实验亲和力，少了一个甲基化衍生物是异常值的情况。这项工作说明了在计算机药物设计中获得可靠的自由能数据的挑战，即使是看似简单的系统，并介绍了一些可用于解决这些问题的技术。
英文摘要：
We apply the Alchemical Transfer Method (ATM) and a bespoke fixed partial charge force field to the SAMPL9 bCD host-guest binding free energy prediction challenge that comprises a combination of complexes formed between five phenothiazine guests and two cyclodextrin hosts. Multiple chemical forms, competing binding poses, and computational modeling challenges pose significant obstacles to obtaining reliable computational predictions for these systems. The phenothiazine guests exist in solution as racemic mixtures of enantiomers related by nitrogen inversions that bind the hosts in various binding poses, each requiring an individual free energy analysis. Due to the large size of the guests and the conformational reorganization of the hosts, which prevent a direct absolute binding free energy route, binding free energies are obtained by a series of absolute and relative binding alchemical steps for each chemical species in each binding pose. Metadynamics-accelerated conformational sampling was found to be necessary to address the poor convergence of some numerical estimates affected by conformational trapping. Despite these challenges, our blinded predictions quantitatively reproduced the experimental affinities for the $β$-cyclodextrin host, less one case of the methylated derivative being an outlier. The work illustrates the challenges of obtaining reliable free energy data in in-silico drug design for even seemingly simple systems and introduces some of the technologies available to tackle them.
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