迈向马尔可夫状态模型的基准：HP35的折叠
Towards a Benchmark for Markov State Models: The Folding of HP35
AI总结：
本文探讨将基于HP35折叠的马尔可夫状态模型作为基准，通过比较不同特征组合、降维和聚类方法测试其鲁棒性，揭示折叠关键特征及模型工作流程要点。
摘要：
采用D. E. Shaw Research发表的villin头piece（HP35）可逆折叠的300微秒长分子动力学（MD）轨迹，我们近期基于残基间接触构建了该折叠过程的马尔可夫状态模型（MSM）[J. Chem. Theory Comput. 2023, 19, 3391]。该模型重现了系统的MD折叠时间，并预测自由能景观的天然态盆地和未折叠区域均被划分为若干结构特征明确的亚稳态子态。鉴于建立定义明确但非平凡的基准问题的必要性，在本展望中，我们研究该MSM在何种程度上以及以何种意义上可作为参考模型。为此，我们通过将MSM与采用不同特征组合、降维方法和聚类方案的模型进行比较来测试其鲁棒性。该研究揭示了HP35折叠的一些主要特征，任何其他有竞争力的系统模型都应重现这些特征。此外，讨论揭示了对于所考虑的问题，MSM工作流程的哪些部分最为重要，并阐明了基于状态的模型在解释生物分子模拟方面的前景和可能的陷阱。
英文摘要：
Adopting a $300 \, μ$s-long molecular dynamics (MD) trajectory of the reversible folding of villin headpiece (HP35) published by D. E. Shaw Research, we recently constructed a Markov state model (MSM) of the folding process based on interresidue contacts [J. Chem. Theory Comput. 2023, ${\bf {19}}$, 3391]. The model reproduces the MD folding times of the system and predicts that both the native basin and the unfolded region of the free energy landscape are partitioned into several metastable substates that are structurally well characterized. Recognizing the need to establish well-defined but nontrivial benchmark problems, in this Perspective we study to what extent and in what sense this MSM may be employed as a reference model. To this end, we test the robustness of the MSM by comparing it to models that use alternative combinations of features, dimensionality reduction methods and clustering schemes. The study suggests some main characteristics of the folding of HP35, which should be reproduced by any other competitive model of the system. Moreover, the discussion reveals which parts of the MSM workflow matter most for the considered problem, and illustrates the promises and possible pitfalls of state-based models for the interpretation of biomolecular simulations.
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