TY - JOUR
T1 - Conformational distributions of isolated myosin motor domains encode their mechanochemical properties
AU - Porter, Justin R.
AU - Meller, Artur
AU - Zimmerman, Maxwell I.
AU - Greenberg, Michael J.
AU - Bowman, Gregory R.
N1 - Funding Information:
This work was funded by National Institutes of Health grants R01GM12400701 (GRB), R01HL141086 (MJG), T32GM02700 (AM), and F30HL146052 (JRP), National Science Foundation CAREER Award MCB-1552471 (GRB), GRB holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund and a Packard Fellowship for Science and Engineering from the David and Lucile Packard Foundation (GRB). MIZ was supported in part by a Monsanto Graduate Fellowship and a Center for Biological Systems Engineering Fellowship.
Funding Information:
We are extremely grateful to the citizen scientists of Folding@home for their generous donation of computing resources. We are also grateful to Prof. Eric Galburt, Prof. John Edwards, and Dr. Joshua Alinger for their insight and helpful comments about this work. We are also grateful to the Center for High Performance Computing at the Mallinkrodt Institute for Radiology for computer time. This work was funded by National Institutes of Health grants R01GM12400701 (GRB), R01HL141086 (MJG), T32GM02700 (AM), and F30HL146052 (JRP), National Science Foundation CAREER Award MCB-1552471 (GRB), GRB holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund and a Packard Fellowship for Science and Engineering from the David and Lucile Packard Foundation (GRB). MIZ was supported in part by a Monsanto Graduate Fellowship and a Center for Biological Systems Engineering Fellowship.
Publisher Copyright:
© Porter et al.
PY - 2020/5
Y1 - 2020/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085855133&partnerID=8YFLogxK
U2 - 10.7554/eLife.55132
DO - 10.7554/eLife.55132
M3 - Article
C2 - 32479265
AN - SCOPUS:85085855133
SN - 2050-084X
VL - 9
JO - eLife
JF - eLife
M1 - e55132
ER -