Biophysical Society Thematic Meeting | Canterbury 2023

Towards a More Perfect Union: Multi-Scale Models of Muscle and Their Experimental Validation

Thursday Speaker Abstracts

MULTISCALE MODELS OF MUSCLE MELDING MOLECULAR AND MYOFILAMENT LEVELS OF ORGANIZATION. Matt Childers 2 ; Travis Tune 1 ; Farid Moussavi-Harami 3 ; Sage Malingen 1,2 ; Jennifer Davis 4 ; Michael Regnier 2 ; Thomas L Daniel 1 ; 1 University of Washington, Biology, Seattle, WA, USA

2 University of Washington, Bioengineering, Seattle, WA, USA 3 University of Washington, Cardiology, Seattle, WA, USA 4 University of Washington, Pathology, Seattle, WA, USA

Force generation by muscle is brought about by the complex interaction among millions of motor proteins interacting in a highly structured compliant lattice of thick and thin filaments. Muscle contractility is therefore a problem of multi-scale physics: it spans scales from the dynamics that occur at few Angstroms to those that characterize entire cells. Importantly, biophysical processes to that occur at the scale of an entire cell or muscle will influence dynamics that govern rate transitions at the scale of single molecules. Similarly, the single molecule processes at the atomic scale determine the larger scale dynamics. To explore this bi-directional interaction across these spatial scales we combine our spatially explicit model of the half sarcomere with an atomistic scale model of thin filament actin monomers exposed to an externally applied force. The force is computed from the spatially inhomogeneous thin filament forces that arise during activation. The largest forces and strains arise at the M-line and near the Z-disk with lower forces occurring in the middle of the thin filament. The local strains, ranging between 0.1 and 0.2% , is used to estimate the work associated with that strain and guides steered MD models. In structures generated from cryoEM models, helical spacings within an unstretched f-actin heptamer gave rise to actin layer lines measuring helical spacings of 6.0 nm and 5.0 nanometers. This disagreed with helical spacings of 5.9 and 5.1 nm measured in x-ray diffraction of muscle under passive tension. In steered MD simulations, bi-directional axial stretch amounting to 27 kcal/mol work was applied to the heptamers to recover the 5.9/5.1 helical spacings observed experimentally. Deformations of the thin filament from the atomistic scale are then compared to those computed for the sarcomere model.

55