Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L.

ABSTRACT: Hypertrophic cardiomyopathy (HCM) is an inherited disorder often caused by mutations to sarcomeric genes. Many different HCM-associated TPM1 mutations have been identified but they vary in their degrees of severity, prevalence, and rate of disease progression. The pathogenicity of many TPM1 variants detected in the clinical population remains unknown. Our objective was to employ a computational modeling pipeline to assess pathogenicity of one such variant of unknown significance, TPM1 S215L, and validate predictions using experimental methods. Molecular dynamic simulations of tropomyosin on actin suggest that the S215L significantly destabilizes the blocked regulatory state while increasing flexibility of the tropomyosin chain. These changes were quantitatively represented in a Markov mode

SUBMITTER: Halder SS 

PROVIDER: S-EPMC9991458 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature