Biophysical Society Thematic Meeting | Canterbury 2023

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

Tuesday Speaker Abstracts

PREDICTING CLINICAL PHENOTYPES OF TPM1 MISSENSE MUTATIONS Stuart G. Campbell 1 ; Saiti Halder 1 ; Michael J Rynkiewicz 2 ; Jeffrey R Moore 3 ; William Lehman 2 ; 1 Yale University, Biomedical Engineering, New Haven, CT, USA 2 Boston University Medical Center, Pharmacology, Physiology, & Biophysics, Boston, MA, USA 3 University of Massachusetts Lowell, Biological Science, Lowell, MA, USA Mutations to the gene encoding human cardiac tropomyosin (TPM1) have been linked with a range of clinically significant inherited cardiomyopathies. Although TPM1 genetic variants can be readily identified through gene sequencing, the mere presence of such a variant is not deemed actionable for the treatment of a patient unless or until additional information on the pathogenicity of the variant can be obtained. Because cost or other factors make it impossible to generate a mouse model or perform linkage analysis for each new TPM1 variant, we have sought a scalable computational approach to evaluate the physiological consequences (and hence pathogenicity) of arbitrary TPM1 missense variants. Our computational pipeline brings together atomistic simulations of the cardiac thin filament, coarse-grain models of tropomyosin bending, and Markov-type models of thin filament regulatory dynamics to make predictions of mutation effects. Simulations of steady-state regulated in vitro motility and isometric twitch dynamics are then validated experimentally. The degree to which quantitative multi-scale predictions are possible is demonstrated through a series of specific cases, including clinically well characterized mutations and attempts to screen several TPM1 variants of unknown significance.

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