In silico and in vitro models reveal the molecular mechanisms of hypocontractility caused by TPM1 M8R.

ABSTRACT: Dilated cardiomyopathy (DCM) is an inherited disorder often leading to severe heart failure. Linkage studies in affected families have revealed hundreds of different mutations that can cause DCM, with most occurring in genes associated with the cardiac sarcomere. We have developed an investigational pipeline for discovering mechanistic genotype-phenotype relationships in DCM and here apply it to the DCM-linked tropomyosin mutation TPM1 M8R. Atomistic simulations predict that M8R increases flexibility of the tropomyosin chain and enhances affinity for the blocked or inactive state of tropomyosin on actin. Applying these molecular effects to a Markov model of the cardiac thin filament reproduced the shifts in Ca²⁺sensitivity, maximum force, and a qualitative drop in coopera

SUBMITTER: Creso JG 

PROVIDER: S-EPMC11392859 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature