Key result
Omecamtiv mecarbil binding to the pre-power stroke state of cardiac myosin inhibits functional motions and potentially affects Pi release based on molecular dynamics simulations.
Why the study?
Does omecamtiv mecarbil modify the intrinsic dynamics of the pre-power stroke state of cardiac myosin?
Does omecamtiv mecarbil modify the intrinsic dynamics of the pre-power stroke state of cardiac myosin?
Atomistic molecular dynamics simulations reveal that omecamtiv mecarbil inhibits functional motions of cardiac myosin in the pre-power stroke state, providing mechanistic insight into its conformational selectivity.
Hypothesis-generating for OM mechanism in HF; leaves open clinical translation of myosin effects.
Omecamtiv mecarbil (OM), currently investigated for the treatment of heart failure, is the first example of a new class of drugs (cardiac myotropes) that can modify muscle contractility by directly targeting sarcomeric proteins. Using atomistic molecular dynamics simulations, we show that the binding of OM to the pre-power stroke state of cardiac myosin inhibits the functional motions of the protein and potentially affects Pi release from the nucleotide binding site. We also show that the changes in myosin ATPase activity induced by a set of OM analogues can be predicted from their relative affinity to the pre-power stroke state compared to the near rigor one, indicating that conformational selectivity plays an important role in determining the activity of these compounds.
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Hashem et al. (2020) studied Heart failure. Omecamtiv mecarbil was evaluated on Functional motions of cardiac myosin and Pi release. Omecamtiv mecarbil binding to the pre-power stroke state of cardiac myosin inhibits functional motions and potentially affects Pi release based on molecular dynamics simulations.
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