What Markov State Models Can and Cannot Do: Correlation versus Path-Based Observables in Protein-Folding Models.
What Markov State Models Can and Cannot Do: Correlation versus Path-Based Observables in Protein-Folding Models.
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DOI：
10.1021/acs.jctc.0c01154
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发表时间：
2021-05-11
影响因子：
5.5
通讯作者：
Zuckerman DM
中科院分区：
文献类型：
--
作者：
Suárez E;Wiewiora RP;Wehmeyer C;Noé F;Chodera JD;Zuckerman DM
基于分子动力学（MD）模拟的统计分析，马尔可夫状态模型（MSMs）被广泛应用于研究蛋白质构象动力学的动力学和途径。这些msm对空间和时间进行了粗粒度配置，从而限制了它们可以在不同的空间和时间分辨率下以高保真度再现的可观测物类型。尽管它们很受欢迎，但对于哪些生物物理观测值可以从这些MSM模型中以稳健和无偏的方式计算出来，以及哪些生物物理观测值受到MSM模型固有的时空粗粒度的影响，人们的理解仍然有限。大多数理论论点和实际有效性测试依赖于长时间平衡动力学，如最慢的弛豫时间尺度和实验观察到的时间相关函数。在这里，我们对经过验证的蛋白质折叠mms的能力进行了广泛的评估，以准确地再现基于路径的观察结果，如平均首次通过时间（MFPTs）和过渡路径机制，与直接轨迹分析相比。我们还评估了最近提出的一类历史增强msm (hamsm)，它利用了标准msm中未考虑的附加信息。最后，我们对msm在研究生物分子构象动力学中的各种问题提供了一些实际指导。简而言之，msm可以精确地再现比滞后时间慢的相关函数，但只有当状态的生存期超过滞后时间时，基于路径的可观测值才能可靠地再现，这是一个更严格的要求。即使在存在短期状态的情况下，我们发现hamms更可靠地再现基于路径的可观测值。
Markov state models (MSMs) have been widely applied to study the kinetics and pathways of protein conformational dynamics based on statistical analysis of molecular dynamics (MD) simulations. These MSMs coarse-grain both configuration space and time in ways that limit what kinds of observables they can reproduce with high fidelity over different spatial and temporal resolutions. Despite their popularity, there is still limited understanding of which biophysical observables can be computed from these MSMs in a robust and unbiased manner, and which suffer from the space-time coarse-graining intrinsic in the MSM model. Most theoretical arguments and practical validity tests for MSMs rely on long-time equilibrium kinetics, such as the slowest relaxation timescales and experimentally observable time-correlation functions. Here, we perform an extensive assessment of the ability of well-validated protein folding MSMs to accuractely reproduce path-based observable such as mean first-passage times (MFPTs) and transition path mechanisms compared to a direct trajectory analysis. We also assess a recently proposed class of history-augmented MSMs (haMSMs) that exploit additional information not accounted for in standard MSMs. We conclude with some practical guidance on the use of MSMs to study various problems in conformational dynamics of biomolecules. In brief, MSMs can accurately reproduce correlation functions slower than the lag time, but path-based observables can only be reliably reproduced if the lifetimes of states exceed the lag time, which is a much stricter requirement. Even in the presence of short-lived states, we find that haMSMs reproduce path-based observables more reliably.
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影响因子：
1.6
作者：
Chodera, John D.;Swope, William C.;Dill, Ken A.
通讯作者：
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作者：
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通讯作者：
CHANDLER, D
影响因子：
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作者：
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通讯作者：
Zuckerman, Daniel M.