Abstract
New strategies for the pharmacological treatment of heart muscle diseases rely on molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. Compared to traditional drugs, direct sarcomeric modulators have reduced side effects and a higher potential to be tailored to specific disease phenotypes. Omecamtiv Mecarbil (OM) is a sarcomeric modulator of cardiac myosin that is currently being tested in clinical trials for the treatment of heart failure. While the overall effect of OM is an increased contractility of the cardiac muscle, its molecular mechanism of action is still elusive. Here, we present an in silico study of the cardiac motor domain bound to OM, where the effects of the drug on the dynamical properties of the protein are investigated for the first time with atomistic resolution using Molecular Dynamics simulations. We found that OM binding has a double effect on myosin dynamics, since a) it induces an increased coupling of the converter and lever arm subdomains to the rest of the protein, resulting in a strong reduction in the amplitude of their motions and b) it rewires the network of dynamic correlations within the motor domain, producing preferential communication pathways between the OM binding site and functional regions in the U50K subdomain. Based on these findings, we suggest that the development of improved drugs could be achieved by changing the balance between the two types of OM-induced effects on myosin dynamics. This research is supported by the British Heart Foundation and the UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim.
Highlights
189-Plat Exploring Folding Features in Protein Structure Prediction Saulo H.P. de Oliveira, Charlotte M
We implemented a sequential approach in SAINT2 akin to cotranslational folding, in which the perturbations are performed on a growing peptide
We performed an unbiased comparison between SAINT2 in its sequential and non-sequential modes, and show that sequential protein structure prediction is faster and more efficient than the traditional non-sequential approach
Summary
We conducted 300 ns allatom molecular dynamics simulations in lipid bilayers to assess the structural rigidity and pore size of the phospholamban TM domain from a reported NMRbased model. 189-Plat Exploring Folding Features in Protein Structure Prediction Saulo H.P. de Oliveira, Charlotte M. We contextualise our results in light of the most recent Critical Assessment of protein Structure Prediction (CASP) experiment, where our postdiction results suggest that SAINT2 can produce models of comparable quality to the state-of-the-art.
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