Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

38-POS Board 38 Modulation of Cardiac Myosin Dynamics by Omecamtiv Mecarbil Shaima Hashem , Matteo Tiberti, Arianna Fornili. Queen Mary University of London, London, United Kingdom.

Cardiac myosin II is an allosteric protein involved in the contraction of the heart muscle. Mutations in this protein are responsible for the emergence of several cardiac diseases like hypertrophic and dilated cardiomyopathies, which can lead to heart failure and sudden cardiac death. Therapies based on small-molecule effectors of myosin have recently started to be explored and they seem promising. In particular, the sarcomeric modulator Omecamtiv Mecarbil (OM) is currently being tested in clinical trials for the treatment of heart failure. The binding site of OM on cardiac myosin has been recently unravelled by X-ray crystallography. The drug was shown to bind to a deep pocket close to key regions of the motor domain involved in the propagation of motion from the actin-binding cleft to the converter and lever arm regions. This suggests that a possible role for OM is to increase the coupling between these regions and hence their efficiency in propagating structural changes. Moreover, the drug was found to induce subtle conformational changes in distant regions close to the ATP binding site of myosin, indicating the presence of allosteric effects. The goal of our project was to study the effect of OM on myosin dynamics in order to elucidate its mechanism of action using molecular modelling and Molecular Dynamics (MD) simulations. In particular, we examined the dynamical correlations between the different structural elements of the motor domain. A stronger coupling was observed between the converter-lever arm domain and the rest of the protein upon OM binding, with preferential pathways connecting the OM binding site and distant regions such as the upper 50K domain. This research is supported by the British Heart Foundation and the UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim.

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