  Adopting a $300 \, \mu$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.
