Towards Simulating Cells of Higher Organisms from the Fundamental Physico-Chemical Principles

One of the key unsolved challenges at the interface of physical and life sciences is to formulate comprehensive computational modeling of cells of higher organisms that is based on microscopic molecular principles of chemistry and physics. Towards addressing this problem, we have developed a unique reactive mechanochemical force-field and software, called MEDYAN (Mechanochemical Dynamics of Active Networks: http://medyan.org).  MEDYAN integrates dynamics of multiple mutually interacting phases: 1) a spatially resolved solution phase is treated using a reaction-diffusion master equation; 2) a polymeric gel phase is both chemically reactive and also undergoes complex mechanical deformations; 3) flexible membrane boundaries interact mechanically and chemically with both solution and gel phases.  In this talk, I will first outline our recent progress in simulating multi-micron scale cytosolic/cytoskeletal dynamics at 1000 seconds timescale, and also highlight the outstanding challenges in bringing about the capability for routine molecular modeling of eukaryotic cells. I will also report on MEDYAN’s applications, in particular, on developing a theory of contractility of actomyosin networks and also characterizing dissipation in cytoskeletal dynamics. With regard to the latter, we devised a new algorithm for quantifying dissipation in cytoskeletal dynamics, finding that simulation trajectories of entropy production provide deep insights into structural evolution and self-organization of actin networks, uncovering earthquake-like processes of gradual stress accumulation followed by sudden rupture and subsequent network remodeling.