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Updated: Jan 18, 2026
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Understanding hypertrophic cardiomyopathy and its regulation by myosin drugs
Ritaban Halder1, Arieh Warshel1
1Department of Chemistry, University of Southern California, Los Angeles, California, USA.
Insights
Hypertrophic cardiomyopathy (HCM) research reveals how the R190T mutation in β-cardiac myosin destabilizes the prepowerstroke state, accelerating phosphate release. This molecular insight informs potential therapeutic strategies for HCM by targeting myosin function.
Area of Science:
- Molecular biology and biophysics
- Cardiovascular research
- Protein dynamics and function
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart disease often caused by mutations in the β-cardiac myosin (MYH7) gene.
- The R190T mutation in MYH7 is linked to cardiac abnormalities and fatal HCM.
- Understanding the molecular mechanisms of MYH7 mutations is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the molecular effects of the HCM-associated R190T mutation in β-cardiac myosin.
- To elucidate how this mutation alters the phosphate release step, a key determinant of myosin function.
- To explore the potential of existing myosin drugs to correct the defects caused by the R190T mutation.
Main Methods:
- All-atom umbrella sampling simulations
- Renormalization simulations
- Binding energy and stability analysis
- Structural and multiple sequence analysis
- Free energy calculations of the phosphate release barrier
Main Results:
- The R190T mutation destabilizes the prepowerstroke (PPS) state of cardiac myosin.
- This destabilization leads to accelerated phosphate release, the rate-determining step in the myosin cycle.
- Aficamten, mavacamten, and omecamtiv were shown to modulate the phosphate release barrier of the mutant myosin.
Conclusions:
- The R190T mutation's impact on the phosphate release barrier is a critical factor in HCM pathogenesis.
- Targeting the phosphate release step offers a potential therapeutic avenue for HCM.
- Multiscale approaches are vital for understanding complex diseases like HCM and developing targeted therapies.
Abstract:
Hypertrophic cardiomyopathy (HCM) is an inherited form of heart disease, caused by specific mutations, many of which are encoded by the β-cardiac myosin (MYH7) protein. This work provides molecular insight into the effect of an HCM-causing mutation, R190T of β-cardiac myosin. The Arginine190 (R190) resides near the active site of the cardiac myosin and its alteration by a threonine (T190) residue leads to cardiac abnormalities related to the fatal HCM. Since the mutations lead to change in the function of the myosin, we focused on our previous finding that the motion and its directionality are determined by the rate-determining barrier, which in the current case is the phosphate release step. Our study of the change of the phosphate release barrier used several approaches, including all-atom umbrella sampling simulations, renormalization simulations, binding energy and stability analysis as well as structural and multiple sequence analysis. Our free energy calculations of the barrier for the rate-determining phosphate release step reproduced the observed effect. Furthermore, we show that three key myosin drugs, aficamten, mavacamten, and omecamtiv, modulate the phosphate release barrier of the faulty myosin, and by this means it could repair the defects of the HCM mutant associated with fast phosphate release. In exploring the reasons for the effects of the mutations and the drugs, we conclude that the R190T mutation leads to the destabilization of the prepowerstroke (PPS) state of cardiac myosin. Such destabilization triggers rapid phosphate release from cardiac myosin. Since phosphate release is the rate-determining step of β-cardiac myosin, such alteration of the phosphate release barrier of the R190T mutant is a crucial functional factor. Our study demonstrates the importance of using multiscale approaches for the revelation of key mechanisms of HCM disease. Furthermore, we provide further evidence of the crucial role of the rate-determining barrier in establishing the overall function of the myosin cycle.
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