Markov State Models: From an Art to a Science

J Am Chem Soc. 2018 Feb 21;140(7):2386-2396. doi: 10.1021/jacs.7b12191. Epub 2018 Feb 2.


Markov state models (MSMs) are a powerful framework for analyzing dynamical systems, such as molecular dynamics (MD) simulations, that have gained widespread use over the past several decades. This perspective offers an overview of the MSM field to date, presented for a general audience as a timeline of key developments in the field. We sequentially address early studies that motivated the method, canonical papers that established the use of MSMs for MD analysis, and subsequent advances in software and analysis protocols. The derivation of a variational principle for MSMs in 2013 signified a turning point from expertise-driving MSM building to a systematic, objective protocol. The variational approach, combined with best practices for model selection and open-source software, enabled a wide range of MSM analysis for applications such as protein folding and allostery, ligand binding, and protein-protein association. To conclude, the current frontiers of methods development are highlighted, as well as exciting applications in experimental design and drug discovery.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Drug Discovery
  • Ligands
  • Markov Chains
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Protein Folding
  • Proteins / chemistry*


  • Ligands
  • Proteins