Conformational distributions of isolated myosin motor domains encode their mechanochemical properties
Open Access
- 29 May 2020
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
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 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
Funding Information
- National Institutes of Health (R01GM12400701)
- National Institutes of Health (R01HL141086)
- National Institutes of Health (T32GM02700)
- National Institutes of Health (F30HL146052)
- National Science Foundation (MCB-1552471)
- Burroughs Wellcome Fund (Career Award at the Scientific Interface)
- David and Lucile Packard Foundation (Fellowship for Science and Engineering)
- Monsanto Company (Graduate Fellowship)
- Washington University in St. Louis (Center for Biological Systems Engineering Fellowship)
This publication has 77 references indexed in Scilit:
- An intermediate along the recovery stroke of myosin VI revealed by X-ray crystallography and molecular dynamicsProceedings of the National Academy of Sciences of the United States of America, 2018
- GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputersSoftwareX, 2015
- Discovery of multiple hidden allosteric sites by combining Markov state models and experimentsProceedings of the National Academy of Sciences of the United States of America, 2015
- An Introduction to Markov State Models and Their Application to Long Timescale Molecular SimulationPublished by Springer Science and Business Media LLC ,2014
- The Superfast Human Extraocular Myosin Is Kinetically Distinct from the Fast Skeletal IIa, IIb, and IId IsoformsOnline Journal of Public Health Informatics, 2013
- Equilibrium fluctuations of a single folded protein reveal a multitude of potential cryptic allosteric sitesProceedings of the National Academy of Sciences of the United States of America, 2012
- Shaking the myosin family tree: Biochemical kinetics defines four types of myosin motorSeminars in Cell & Developmental Biology, 2011
- The structural basis of blebbistatin inhibition and specificity for myosin IINature Structural & Molecular Biology, 2005
- The Protein Data BankNucleic Acids Research, 2000
- GROMACS: A message-passing parallel molecular dynamics implementationComputer Physics Communications, 1995