  Myosin-V is a highly processive dimeric protein that walks with 36nm steps
along actin tracks, powered by coordinated ATP hydrolysis reactions in the two
myosin heads. No previous theoretical models of the myosin-V walk reproduce all
the observed trends of velocity and run-length with [ADP], [ATP] and external
forcing. In particular, a result that has eluded all theoretical studies based
upon rigorous physical chemistry is that run length decreases with both
increasing [ADP] and [ATP]. We systematically analyse which mechanisms in
existing models reproduce which experimental trends and use this information to
guide the development of models that can reproduce them all. We formulate
models as reaction networks between distinct mechanochemical states with
energetically determined transition rates. For each network architecture, we
compare predictions for velocity and run length to a subset of experimentally
measured values, and fit unknown parameters using a bespoke MCSA optimization
routine. Finally we determine which experimental trends are replicated by the
best-fit model for each architecture. Only two models capture them all: one
involving [ADP]-dependent mechanical detachment, and another including
[ADP]-dependent futile cycling and nucleotide pocket collapse. Comparing
model-predicted and experimentally observed kinetic transition rates favors the
latter.
