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.
Highlights
Myosin motors (Figure 1A) perform an extraordinary diversity of biological functions despite sharing a common mechanochemical cycle
Two important and highly variable parameters for motor function are the rate of ADP release, which sets the speed of movement along actin, and the duty ratio, which is the fraction of time a myosin spends attached to actin during one full pass through its mechanochemical cycle
Analyzing our Markov state models (MSMs), we find they capture sufficient information about myosin motor domains’ thermodynamics and kinetics to produce reasonable estimates of duty ratio and ADP release rates
Summary
Myosin motors (Figure 1A) perform an extraordinary diversity of biological functions despite sharing a common mechanochemical cycle. Myosin-II motors power muscle contraction, whereas myosin-V motors engage in intracellular transport This diversity is in part due to differences in myosins’ tails and light chain-binding domains, which influence properties like localization and multimerization (Krendel and Mooseker, 2005). Some of this diversity is encoded in the motor domains themselves (Greenberg et al, 2016) These differences stem from variations in the tunings of the thermodynamics and kinetics of the individual steps of the myosins’ conserved mechanochemical cycle, which couples ATP hydrolysis to actin binding and the swing of a lever arm (De La Cruz and Ostap, 2004). In muscle, myosin-II motors are arranged into multimeric arrays called thick filaments and the individual motors typically have a strong preference for the actin free state (i.e., low duty ratio). The speed of myosin movement along actin (in the absence of opposing forces) is set by the rate of ADP dissociation (De La Cruz and Ostap, 2004), and it varies by four orders of magnitude from ~0.4 s-1 for non-muscle myosin-IIb (Nagy et al, 2013) to >2800 s-1 for myosin-XI (Ito et al, 2007)
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