Biophysical Society Thematic Meeting | Canterbury 2023

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

Poster Abstracts

14-POS Board 14 MOLECULAR DYNAMICS SIMULATIONS REVEAL FUNCTIONAL CHANGES IN TROPONIN RESULTING FROM MUTATIONS IMPLICATED IN CARDIOMYOPATHIES Sage A Malingen 1,2 ; Matthew C Childers 1,2 ; Travis Tune 2,3 ; Kerry Kao 1,2 ; Thomas Daniel 2,3 ; Farid Moussavi-Harami 2,4,5 ; Michael Regnier 1,2 ; 1 University of Washington, Bioengineering, Seattle, WA, USA 2 University of Washington, Center for Translational Muscle Research, Seattle, WA, USA 3 University of Washington, Biology, Seattle, WA, USA 4 University of Washington, Laboratory Medicine & Pathology, Seattle, WA, USA 5 University of Washington, Division of Cardiology, Seattle, WA, USA Sarcomeric proteins function in concert to power muscle contraction, but mutations to individual components can cause organ-scale dysfunction, such as hypertrophic and dilated cardiomyopathies. Here we consider troponin, which regulates the formation of actomyosin cross-bridges via a calcium-mediated shape change that leads to thin filament activation. We have used molecular dynamics simulations to elucidate how troponin's structure changes for a series of mutations in troponin C implicated in hypertrophic and dilated cardiomyopathies. By simulating all three subunits of the troponin complex, we retain the connected structure of the protein, allowing the impact of a point mutation to propagate throughout the protein. These models underscore that impairment in calcium binding and alterations in TnI's interaction with the hydrophobic patch of TnC lead to dysfunction. Further, we are deploying steered molecular dynamics to inform how mutations in the N lobe of cardiac troponin C alter calcium affinity and the interaction of the switch peptide with the hydrophobic patch. Ultimately, these steered molecular dynamics results can inform a spatially explicit model of the half sarcomere to predict how twitches change when troponin is mutated, bridging between the molecular scale and the emergent behavior of the half sarcomere.

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