Computational modeling of cooperative regulation of both strands in thin filaments.

Abstract

Striated muscle contraction is regulated by thin filaments in response to changes of cytoplasmic Ca2+ concentration. Thin filaments are comprised of ∼27 pairs of regulatory units (RUs), each RU having 7 actins, 1 tropomyosin and 1 troponin. Cooperative interactions between adjacent RUs along thin filaments have been extensively considered, but RUs across thin filaments have received little attention. We used FiberSim—a spatially explicit computational model of the striated muscle sarcomere that includes myofilament compliance (Kosta et al. 2022 Biophs J)—modified to include interactions among neighboring RUs along and across thin filaments. We first simulated Ca2+-dependent changes in thin filaments in the absence of cross-bridges at systolic Ca2+ levels (∼50% activation) with cooperative parameters based on cryo-EM of porcine cardiac thin filaments (Risi et al. 2021 PNAS). Statistical distribution of RU states was analyzed in R as described for cryo-EM data, which allowed comparison between probability matrices obtained from FiberSim simulation and cryo-EM. It shows that FiberSim mimics the probability distribution pattern of RU states obtained from cryo-EM under three conditions: (1) RU on the upper strand is activated; (2) RU on lower strand is activated; (3) RU on lower strand is inactivated. However, the probability distribution exhibits opposite trend when RU on the upper strand is inactivated, which could be explained by the unspecified strand position in the model. Second, isometric force-pCa relationships were simulated using the fitted cooperative parameters, and compared with absence of cooperativity. Results show slightly lower cooperativity because of negative cooperativity across thin filaments. This initial computational modeling of cooperativity that considers RUs both along and across thin filaments aims to bridge structural and functional analyses.