Conformational distributions of isolated myosin motor domains encode their mechanochemical properties

Elife. 2020 May 29;9:e55132. doi: 10.7554/eLife.55132.


Myosin motor domains perform an extraordinary diversity of biological functions despite sharing a common mechanochemical cycle. Motors are adapted to their function, in part, by tuning the thermodynamics and kinetics of steps in this cycle. However, it remains unclear how sequence encodes these differences, since biochemically distinct motors often have nearly indistinguishable crystal structures. We hypothesized that sequences produce distinct biochemical phenotypes by modulating the relative probabilities of an ensemble of conformations primed for different functional roles. To test this hypothesis, we modeled the distribution of conformations for 12 myosin motor domains by building Markov state models (MSMs) from an unprecedented two milliseconds of all-atom, explicit-solvent molecular dynamics simulations. Comparing motors reveals shifts in the balance between nucleotide-favorable and nucleotide-unfavorable P-loop conformations that predict experimentally measured duty ratios and ADP release rates better than sequence or individual structures. This result demonstrates the power of an ensemble perspective for interrogating sequence-function relationships.

Keywords: biochemistry; chemical biology; chicken; conformational heterogeneity; dictyostelium; energy landscapes; human; machine learning; markov sate models; molecular biophysics; molecular dynamics; structural biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Diphosphate / chemistry
  • Adenosine Diphosphate / metabolism
  • Animals
  • Avian Proteins / chemistry
  • Avian Proteins / genetics
  • Avian Proteins / metabolism
  • Biomechanical Phenomena / genetics
  • Chickens
  • Humans
  • Kinetics
  • Molecular Dynamics Simulation
  • Myosins / chemistry*
  • Myosins / genetics
  • Myosins / metabolism*
  • Protein Conformation
  • Protein Domains
  • Thermodynamics


  • Avian Proteins
  • Adenosine Diphosphate
  • Myosins