Computational modeling of cytoskeleton-cytoplasm mechanics at the mesoscale

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Cell mechanics is largely determined by the cytoskeleton, which is a dynamic mesh made of semiflexible fibers such as actin filaments, as well as multiple types of cross linking proteins, and molecular motors such as myosin. The fundamental problem addressed in this project is to understand the connections between structure, dynamics, and function of the cytoskeleton. It is not yet known if microscopic filaments can self-organize into the macroscopic chiral structures responsible for left-right asymmetry seen in some tissues, or why networks of actin gels are typically contractile (with or without molecular motors like myosin). The stochastic nature of sub-cellular processes coupled with the ever-changing topology of cytoskeletal networks make these questions difficult or impossible to interrogate through lab measurements or existing simulation techniques. This project will develop computational tools required to close this knowledge gap; tools which carefully capture the microscopic features of cellular fiber networks, at the extraordinary computational scale required to probe their macroscopic structure. The goal is to derive a macroscopic hydrodynamics-like theory from the numerical simulations of the cytoskeletal gels that will allow PI to simulate whole-cell mechanochemical phenomena, like cytokinesis. Education and outreach activities related to this project will include learning modules focused on cell mechanics simulation and biological fluids, implemented in both summer research experience programs for undergraduates and after school programs at New York area middle schools.The goal of this project is to answer five fundamental questions in cellular biology: (1) What are the (hydro)mechanical properties of cross-linked actin networks? (2) Why are actin-myosin gels usually contractile? (3) Can microscopic twists of actin filaments self-organize into macroscopic chiral structures? (4) How much do thermal forces contribute to the viscoelastic gel moduli? (5) Can thermal forces transduce random microscopic twists and bends of actin filaments into macroscopic gel contraction without myosin? To interrogate these questions, the team will develop novel numerical methods which utilize creative representations of fibers to directly enforce their inextensiblity and describe the local twist along their length. The methods will reconcile the hydrodynamics of both passive and active filaments with fluctuations from the surrounding cytosol, in addition to carefully accounting for intra-network dynamics from the motion of molecular motors and dynamically binding/unbinding cross-linkers. The team will employ efficient, iterative linear algebra to compute fiber dynamics in linear time in the number of fibers, enabling unprecedented simulations of the cellular cytoskelton. The team will develop spectrally-accurate Chebyschev discretizations of semi-flexible fibers that dramatically reduce the total degrees of freedom needed to describe a single filament, and implement them in efficient, parallel, public-domain codes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.