炼金术转移和平均力势法在SAMPL8主客盲态挑战中的应用
Application of the Alchemical Transfer and Potential of Mean Force Methods to the SAMPL8 Host-Guest Blinded Challenge
摘要：
我们报告了我们参与SAMPL8 GDCC盲法挑战的结果，用于预测主客体结合亲和力。绝对结合亲和力预测对于分子缔合和药物发现的生物物理学具有核心重要性。盲法SAMPL系列为客观评价结合自由能方法的可靠性提供了一个重要的论坛。在这个盲态挑战中，我们采用了两种结合自由能方法，新开发的炼金术转移方法（ATM）和成熟的平均力势（PMF）物理途径方法，使用相同的设置和力场模型。从两种方法计算的结合自由能是在良好的定量协议。重要的是，还发现两种方法的结果与随后释放的实验结合亲和力一致，$R^2$为0.89（ATM）和0.83（PMF）。鉴于这两种自由能方法是基于完全不同的热力学途径，这两种方法的结果之间的密切协议和它们与实验结合自由能的一般协议是一个证明的理论和方法实现的高品质。该研究提供了新的ATM结合自由能估计协议的进一步验证，它铺平了道路，以进一步扩展的方法更复杂系统。
英文摘要：
We report the results of our participation in the SAMPL8 GDCC Blind Challenge for host-guest binding affinity predictions. Absolute binding affinity prediction is of central importance to the biophysics of molecular association and pharmaceutical discovery. The blinded SAMPL series have provided an important forum for assessing the reliability of binding free energy methods in an objective way. In this blinded challenge, we employed two binding free energy methods, the newly developed alchemical transfer method (ATM) and the well-established potential of mean force (PMF) physical pathway method, using the same setup and force field model. The calculated binding free energies from the two methods are in excellent quantitative agreement. Importantly, the results from the two methods were also found to agree well with the experimental binding affinities released subsequently, with an $R^2$ of 0.89 (ATM) and 0.83 (PMF). Given that the two free energy methods are based on entirely different thermodynamic pathways, the close agreement between the results from the two methods and their general agreement with the experimental binding free energies are a testament to the high quality achieved by theory and methods. The study provides further validation of the novel ATM binding free energy estimation protocol and it paves the way to further extensions of the method to more complex systems.
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