Conformational distributions of isolated myosin motor domains encode their mechanochemical properties
Year: 2019
Type: preprint
Abstract: 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 twelve 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. Subject Areas Biochemistry and Chemical Biology, Structural Biology and Molecular Physics
Authors: Justin R. Porter, Artur Meller, Maxwell I. Zimmerman, Michael J. Greenberg, Gregory R. Bowman
Institution: Washington University in St. Louis
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Allosteric impact of non-active-site mutations on enzymatic function, G1956509553, CAREER: FAST methods for protein folding and design, G5939431379, G6671297155, Physics-based precision medicine: computationally phenotyping myosin isoforms and cardiomyopathy mutations, G7953506208, Regulation of cardiac power output in health and disease
OpenAlex ID: W2996613686