Modeling Hypertrophic Cardiomyopathy-Related MYH7 Variants: Insights into Structural Changes and Cardiovascular...

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Computational Biology

Background:

• Mutations in the MYH7 gene, encoding β-myosin heavy chain (β-MHC), are a primary cause of hypertrophic cardiomyopathy (HCM).
• Patient responses to targeted therapies like mavacamten, a cardiac myosin inhibitor, vary significantly due to these genetic variants.
• Understanding genotype-specific drug interactions is crucial for personalized HCM treatment.

Purpose of the Study:

• To investigate the structural impact of MYH7 mutations on β-MHC.
• To evaluate how these mutations influence the binding affinity of the cardiac myosin inhibitor mavacamten.
• To explore potential genotype-tailored therapeutic strategies for HCM.

Main Methods:

• Utilized AlphaFold modeling to generate structural models of wild-type (WT) and mutant β-MHC.
• Performed molecular docking to assess mavacamten binding affinity for 22 MYH7 variants.
• Employed molecular dynamics (MD) simulations and MM/PBSA calculations for in-depth analysis of selected variants.

Main Results:

• Identified specific MYH7 mutations (Arg719Trp, Arg723Gly) that appear to enhance mavacamten binding.
• Found that the Gly741Trp mutation significantly disrupts mavacamten binding affinity.
• Observed that Arg453Cys and Thr1377Met variants, despite increased flexibility, maintained favorable drug interaction profiles.

Conclusions:

• Specific MYH7 mutations differentially modulate mavacamten binding to β-MHC.
• Computational modeling provides valuable insights into genotype-dependent drug efficacy in HCM.
• Findings support the development of personalized treatment approaches for hypertrophic cardiomyopathy based on individual genetic profiles.