What to Make of Zero: Resolving the Statistical Noise from Conformational Reorganization in Alchemical Binding Free Energy Estimates with Metadynamics Sampling
What to Make of Zero: Resolving the Statistical Noise from Conformational Reorganization in Alchemical Binding Free Energy Estimates with Metadynamics Sampling
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DOI：
10.1021/acs.jctc.3c01250
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发表时间：
2024-01-22
影响因子：
5.5
通讯作者：
Gallicchio，Emilio
中科院分区：
文献类型：
--
作者：
Khuttan，Sheenam;Gallicchio，Emilio
引入自相对结合自由能（self-RBFE）方法来评估双拓扑炼金术结合自由能估计器的固有统计方差。self-RBFE是配体与同一配体的副本之间的相对结合自由能，其真实值为零。然而，由于配体的两个拷贝是独立运动的，有限长度模拟产生的自rbfe值是波动的，可以用来测量模型的方差。这一验证的结果提供了证据，证明在基准研究中观察到的很大一部分误差反映了未收敛估计的统计波动，而不是模型的准确性。此外，我们发现配体重组是结合自由能估计统计方差的一个重要因素，并且配体扭转自由度的元动力学加速构象采样可以大大缩短收敛时间。
We introduce the self-relative binding free energy (self-RBFE) approach to evaluate the intrinsic statistical variance of dual-topology alchemical binding free energy estimators. The self-RBFE is the relative binding free energy between a ligand and a copy of the same ligand, and its true value is zero. Nevertheless, because the two copies of the ligand move independently, the self-RBFE value produced by a finite-length simulation fluctuates and can be used to measure the variance of the model. The results of this validation provide evidence that a significant fraction of the errors observed in benchmark studies reflect the statistical fluctuations of unconverged estimates rather than the models’ accuracy. Furthermore, we find that ligand reorganization is a significant contributing factor to the statistical variance of binding free energy estimates and that metadynamics-accelerated conformational sampling of the torsional degrees of freedom of the ligand can drastically reduce the time to convergence.