Biophysical Society Thematic Meeting | Canterbury 2023

Towards a More Perfect Union: Multi-Scale Models of Muscle and Their Experimental Validation

Poster Abstracts

1-POS Board 1 COMPUTATIONAL INSIGHTS INTO THE EFFECT OF MAVACAMTEN ON THE ATP HYDROLYSIS STEP OF THE HUMAN CARDIAC BETA MYOSIN Ananya Chakraborti 1 ; Jil C Tardiff 2 ; Steven D Schwartz 1 ; 1 University of Arizona, Department of Chemistry and Biochemistry, Tucson, AZ, USA 2 University of Arizona, Department of Biomedical Engineering, Tucson, AZ, USA Mavacamten is a cardiac specific allosteric modulator observed to inhibit myosin ATPase activity. It directly binds to cardiac beta myosin altering multiple steps of the cross-bridge cycle. In this detailed study, we aimed to explore the atomistic alterations in the ATP hydrolysis step of the human cardiac beta myosin due to the presence of Mavacamten using the rare-event method Transition Path Sampling. The crystal structures of the Mavacamten-bound myosin are not yet available and hence, we have utilized the molecular docking approach to develop the initial probable structure of the same in the pre-powerstroke conformation. We then generated unbiased thermodynamic ensemble of reactive trajectories for the breakdown of ATP to Adenosine diphosphate (ADP) and Hydrogen Phosphate (HPO 4 2- ). Our results were able to predict the variations due to Mavacamten, in the active site as well as the general pathway of the hydrolysis reaction and the transition states involved. We have also included the mutant forms of myosin causing genetic cardiomyopathies: R712L and P710R to detect the effect of the drug on the mutation-induced changes in the chemical step. These molecular insights are essential to understand the drug action and hence, aid in their targeted applications.

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