(508d) Ultra-Coarse-Grained Modeling of ATP Hydrolysis in an Actin Filament | AIChE

(508d) Ultra-Coarse-Grained Modeling of ATP Hydrolysis in an Actin Filament


Katkar, H. H. - Presenter, The University of Chicago
Voth, G. A., The University of Chicago
Actin is a critical component of the cellular cytoskeleton in which it forms polar filaments that are dynamic in nature. The actin sub-unit in a filament is bound to the nucleotide ATP that hydrolyzes as the filament ages. Aging of the filament, and hence ATP hydrolysis, modulates the long length scale physical network properties and dynamics critical to the function of the cytoskeleton. ATP hydrolysis occurs at a timescale of a few seconds, when ATP is converted to an intermediate ADP with a bound inorganic phosphate. The release of inorganic phosphate is even slower, and occurs at a timescale of a few minutes. These timescales are too slow to be studied using atomistic simulations.

We present a systematic multi-scale ultra-coarse-graining (UCG) approach that provides a computationally efficient way to simulate a long actin filament undergoing ATP hydrolysis, while rigorously taking into account relevant atomistic details. A systematic procedure is used to construct a heterogeneous elastic network model for the filament including the implicit representation of sub-unit specific states of the bound nucleotide, using information from underlying atomistic simulations of short actin filaments. The elastic network is enforced to be short-ranged by restricting the harmonic bonds between coarse-grained sites to two neighboring actin sub-units. The slower conformational and chemical changes associated with the hydrolysis of ATP and the phosphate release are simulated with the UCG modeling approach by assigning internal states to the coarse-grained sites. Transitions between the three states, each represented by a unique potential surface of a local heterogeneous elastic network, are simulated via stochastic transitions coupled to the positions of the coarse-grained sites, and hence to the conformations of the underlying reference atomistic system. The UCG model guarantees detailed balance and is tuned to reproduce experimental reaction rates. The model accurately reproduces long length scale properties such as persistence length of the filament in spite of the local nature of interactions, and is used to systematically study the mechanism of ATP hydrolysis cooperativty in the filament.