Toward a Benchmark for Markov State Models: The Folding of HP35

Adopting a 300 & mu;s long MD trajectory of the foldingof villinheadpiece (HP35) by D. E. Shaw Research, we recently constructed aMarkov state model (MSM) based on inter-residue contacts. The modelreproduces the folding time and predicts that the native basin andunfolded region consist of metastable substates that are structurallywell-characterized. Recognizing the need to establish well-definedbenchmark problems, we study to what extent and in what sense thisMSM can be employed as a reference model. Hence, we test the robustnessof the MSM by comparing it to models that use alternative combinationsof features, dimensionality reduction methods, and clustering schemes.The study suggests some main characteristics of the folding of HP35that should be reproduced by other competitive models. Moreover, thediscussion reveals which parts of the MSM workflow matter most forthe considered problem and illustrates the promises and pitfalls ofstate-based models for the interpretation of biomolecular simulations.