论文标题
通过渐近分析了解MBAR中的错误源
Understanding the Sources of Error in MBAR through Asymptotic Analysis
论文作者
论文摘要
分子动力学中常用的多种采样策略,例如伞状采样和炼金术自由能法,涉及从多种热力学状态采样。通常,将数据重新组合以构建自由能的估计值,并使用多态Bennett接受率(MBAR)形式主义构建平均值。但是,MBAR估计器的误差尚未得到充分理解:MBAR的先前错误分析是独立的样本,并且不允许将总误差归因于单个热力学状态。在这项工作中,我们为MBAR估算得出了一种新颖的中心限制定理。该中心限制定理产生一个误差估计器,可以将其分解为用于采样状态的单个马尔可夫链的贡献。我们证明了在二维中对丙氨酸二肽进行伞采样计算的误差估计器,以及甲烷的水合自由能的炼金计算。在这两种情况下,各州对错误的个人贡献都可以洞悉模拟错误源。我们的数值结果表明,马尔可夫链在单个热力学状态中脱摩所所需的时间对总MBAR误差有很大贡献。此外,它们表明,有可能使用贡献来调整采样并提高MBAR计算的准确性。
Multiple sampling strategies commonly used in molecular dynamics, such as umbrella sampling and alchemical free energy methods, involve sampling from multiple thermodynamic states. Commonly, the data are then recombined to construct estimates of free energies and ensemble averages using the Multistate Bennett Acceptance Ratio (MBAR) formalism. However, the error of the MBAR estimator is not well-understood: previous error analysis of MBAR assumed independent samples and did not permit attributing contributions to the total error to individual thermodynamic states. In this work, we derive a novel central limit theorem for MBAR estimates. This central limit theorem yields an error estimator which can be decomposed into contributions from the individual Markov chains used to sample the states. We demonstrate the error estimator for an umbrella sampling calculation of the alanine dipeptide in two dimensions and an alchemical calculation of the hydration free energy of methane. In both cases, the states' individual contributions to the error provide insight into the sources of error of the simulations. Our numerical results demonstrate that the time required for the Markov chain to decorrelate in individual thermodynamic states contributes considerably to the total MBAR error. Moreover, they indicate that it may be possible to use the contributions to tune the sampling and improve the accuracy of MBAR calculations.