Journal Article

Conformational distributions of isolated myosin motor domains encode their mechanochemical properties

Porter, Justin R, Greenberg, Michael J, Meller, Artur, Bowman, Gregory R, Zimmerman, Maxwell I

2020

Overview

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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Adenosine Diphosphate - chemistry / Adenosine Diphosphate - metabolism / Analysis / Animals / Avian Proteins - chemistry / Avian Proteins - genetics / Avian Proteins - metabolism / Binding sites / Biochemistry / Biochemistry and Chemical Biology / Biomechanical Phenomena - genetics / Cardiomyopathy / Chickens / conformational heterogeneity / Crystal structure / energy landscapes / Humans / Hypotheses / Kinetics / Machine learning / markov sate models / Molecular dynamics / Molecular Dynamics Simulation / Muscle proteins / Mutation / Myosin / Myosins - chemistry / Myosins - genetics / Myosins - metabolism / Phenotypes / Phylogenetics / Power (Philosophy) / Protein Conformation / Protein Domains / Proteins / Simulation / Structural Biology and Molecular Biophysics / Thermodynamics