Leveraging a Separation of States Method for Relative Binding Free Energy Calculations in Systems with Trapped Waters

IF 5.5 1区 化学 Q2 CHEMISTRY, PHYSICAL
Swapnil Wagle, Pascal T. Merz, Yunhui Ge, Christopher I. Bayly and David L. Mobley*, 
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引用次数: 0

Abstract

Methods for calculating the relative binding free energy (RBFE) between ligands to a target protein are gaining importance in the structure-based drug discovery domain, especially as methodological advances and automation improve accuracy and ease of use. In an RBFE calculation, the difference between the binding affinities of two ligands to a protein is calculated by transforming one ligand into another, in the protein–ligand complex, and in solvent. Alchemical binding free energy calculations are often used for such ligand transformations. Such calculations are not without challenges, however; for example, it can be challenging to handle interfacial waters when these play a crucial role in mediating protein–ligand binding. In some cases, the exchange of the interfacial waters with solvent water might be very infrequent in the course of typical molecular simulations, and such interfacial waters can be considered trapped on the simulation time scale. In these cases, RBFE calculation between two ligands, where one ligand binds with a trapped water while the other ligand displaces it, can result in inaccuracies if the surrounding water structure is not sampled adequately for both ligands. So far, a popular choice for treating the trapped waters in RBFE calculations is to combine free energy calculations with enhanced sampling methods that insert/delete waters in the binding site. Despite recent developments in the enhanced sampling methods, they can result in hysteresis in the RBFE estimate, depending on whether the simulations were started with or without the trapped waters. In this study, we introduce an alternative method, separation of states, to calculate the RBFE between ligand pairs where the ligands bind to the protein with different numbers/positions of trapped waters. The separation of states approach treats the sampling of the trapped waters separately from the free energy calculation of the ligand transformation. In our method, a trapped water in protein’s binding site is decoupled from the system first, and the cavity created by its decoupling is stabilized. We then grow a larger ligand into this cavity– a ligand that is known to displace the trapped water. In this study, we show that our method results in precise and accurate estimates of RBFEs for ligand pairs involving the rearrangement of trapped water via RBFE calculations for five such ligand pairs. We have optimized our simulation protocol to be suited for large distributed computational resources and have automated our RBFE calculation workflow.

利用状态分离法计算困水系统中的相对束缚自由能
计算配体与靶蛋白之间的相对结合自由能(RBFE)的方法在基于结构的药物发现领域变得越来越重要,特别是随着方法的进步和自动化提高了准确性和易用性。在RBFE计算中,通过在蛋白质-配体复合物和溶剂中将一种配体转化为另一种配体来计算两种配体对蛋白质的结合亲和力之间的差异。炼金术结合自由能计算常用于这种配体转化。然而,这样的计算并非没有挑战;例如,当界面水在介导蛋白质-配体结合中起关键作用时,处理界面水可能具有挑战性。在某些情况下,在典型的分子模拟过程中,界面水与溶剂水的交换可能非常罕见,这种界面水可以认为在模拟时间尺度上被捕获。在这些情况下,两个配体之间的RBFE计算,其中一个配体与被捕获的水结合,而另一个配体取代它,如果周围的水结构没有为两个配体充分采样,可能会导致不准确。到目前为止,在RBFE计算中处理截留水的一种流行选择是将自由能计算与在结合位点插入/删除水的增强采样方法相结合。尽管最近改进的采样方法有所发展,但它们可能导致RBFE估计的滞后,这取决于模拟是在有或没有被困水的情况下开始的。在这项研究中,我们引入了另一种方法,状态分离,来计算配体对之间的RBFE,其中配体与具有不同数量/位置的捕获水的蛋白质结合。状态分离方法将捕获水的采样与配体转换的自由能计算分开处理。在我们的方法中,捕获在蛋白质结合位点的水首先与系统解耦,并且由其解耦产生的空腔是稳定的。然后,我们在这个腔中植入一个更大的配体——一个已知可以取代被困水的配体。在这项研究中,我们表明,我们的方法通过对五对这样的配体对的RBFE计算,可以精确和准确地估计涉及捕获水重排的配体对的RBFE。我们已经优化了我们的模拟协议,以适应大型分布式计算资源,并自动化了我们的RBFE计算工作流。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Chemical Theory and Computation
Journal of Chemical Theory and Computation 化学-物理:原子、分子和化学物理
CiteScore
9.90
自引率
16.40%
发文量
568
审稿时长
1 months
期刊介绍: The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.
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