Molecular modeling and dynamics studies on implications of mutations in human cardiac beta myosin

Objectives: The aim of study was to predict three dimensional structure of human cardiac beta myosin heavy chain (MYH7) and perform the structure function analysis of the mutations using in silico approaches.

Background: Hypertrophic cardiomyopathy (HCM) is a cardiac disease characterized by left ventricular hypertrophy with the predominant involvement of interventricular septum in the absence of other causes of hypertrophy. Numerous mutations in the sarcomeric genes that cause HCM have been described. MYH7 is the most common gene that has been reported to mutate in HCM, resulting in its aberrant in function.

Methods and Results: Primary and secondary structure analysis of MYH7 revealed that protein is rich in motifs for post translational modifications, helices and is predominantly hydrophobic in character. Homology derived three dimensional structure of head of MYH7 was generated using MODELLER 9v1. The model was validated for its correct stereochemistry using PROCHECK package. The modeled structure was refined by performing energy minimization using AMBER. The predicted structure of MYH7 also shows predominance of helices in MYH7, supporting secondary structure analysis. Molecular dynamics simulations were performed with ff03 force field in explicit solvent environment. The conformational changes in MYH7 wild type vis-a-vis its mutants are discussed.

Conclusion: Three dimensional model of MYH7 has been generated and implications of mutations on the structure and function are reported.