Compressive and Tensile Deformations Alter ATP Hydrolysis and Phosphate Release Rates in Actin Filaments

Actin filament networks in eukaryotic
cells are constantly remodeled
through nucleotide state controlled interactions with actin binding
proteins, leading to macroscopic structures such as bundled filaments,
branched filaments, and so on. The nucleotide (ATP) hydrolysis, phosphate
release, and polymerization/depolymerization reactions that lead to
the formation of these structures are correlated with the conformational
fluctuations of the actin subunits at the molecular scale. The resulting
structures generate and experience varying levels of force and impart
cells with several functionalities such as their ability to move,
divide, transport cargo, etc. Models that explicitly connect the structure
to reactions are essential to elucidate a fundamental level of understanding
of these processes. In this regard, a bottom-up Ultra-Coarse-Grained
(UCG) model of actin filaments that can simulate ATP hydrolysis, inorganic
phosphate release (Pi), and depolymerization reactions is presented
in this work. In this model, actin subunits are represented using
coarse-grained particles that evolve in time and undergo reactions
depending on the conformations sampled. The reactions are represented
through state transitions, with each state represented by a unique
effective coarse-grained potential. Effects of compressive and tensile
strains on the rates of reactions are then analyzed. Compressive strains
tend to unflatten the actin subunits, reduce the rate of ATP hydrolysis,
and increase the Pi release rate. On the other hand, tensile strain
flattens subunits, increases the rate of ATP hydrolysis, and decrease
the Pi release rate. Incorporating these predictions into a Markov
State Model highlighted that strains alter the steady-state distribution
of subunits with ADPPi and ADP nucleotide, thus identifying possible
additional factors underlying the cooperative binding of regulatory
proteins to actin filaments.