Heart Failure Drug Modifies the Intrinsic Dynamics of the Pre-Power Stroke State of Cardiac Myosin

Hashem, Shaima; Davies, William George; Fornili, Arianna

doi:10.1021/acs.jcim.0c00953

Cited by 5 publications

(20 citation statements)

References 35 publications

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“…Studies have revealed that 31% HCM mutations are located in the motor domain of myosin, such as E483K, E774V, and S782N . By designing small ligands that enhance or interfere the allosteric pathway, , we might be able to mitigate the damage resulted from these HCM mutations.…”

Section: Resultsmentioning

confidence: 99%

Exploring the Super-Relaxed State of Human Cardiac β-Myosin by Molecular Dynamics Simulations

li,

Hu,

Wang

2024

J. Phys. Chem. B

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Human β-cardiac myosin plays a critical role in generating the mechanical forces necessary for cardiac muscle contraction. This process relies on a delicate dynamic equilibrium between the disordered relaxed state (DRX) and the super-relaxed state (SRX) of myosin. Disruptions in this equilibrium due to mutations can lead to heart diseases. However, the structural characteristics of SRX and the molecular mechanisms underlying pathogenic mutations have remained elusive. To bridge this gap, we conducted molecular dynamics simulations and free energy calculations to explore the conformational changes in myosin. Our findings indicate that the size of the phosphate-binding pocket can serve as a valuable metric for characterizing the transition from the DRX to SRX state. Importantly, we established a global dynamic coupling network within the myosin motor head at the residue level, elucidating how the pathogenic mutation E483K impacts the equilibrium between SRX and DRX through allosteric effects. Our work illuminates molecular details of SRX and offers valuable insights into disease treatment through the regulation of SRX.

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Section: Resultsmentioning

confidence: 99%

Exploring the Super-Relaxed State of Human Cardiac β-Myosin by Molecular Dynamics Simulations

li,

Hu,

Wang

2024

J. Phys. Chem. B

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“…[ 17 ] (PR) and Ref. [ 14 ] (PPS). The starting structures subjected to energy minimisation will be indicated with the PDB ID used for their generation followed by a * symbol and used as references in some of the analyses.…”

Section: Methodsmentioning

confidence: 99%

“…Energy minimization and equilibration to T = 300 K and p = 1 bar were run with the protocol and parameters described in Ref. [ 14 ] and [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…OM has been shown to bind myosin in both the PR [ 12 ] ( Fig 1A ) and the PPS [ 13 ] ( Fig 1B ) conformations. While its affinity for the PPS state is stronger [ 13 , 14 ], and its mechanism of action has been linked to its ability to stabilise the PPS and subsequent states in the actomyosin cycle [ 13 , 15 ], the existence of a OM-bound PR structure indicates that the site can be targeted by small molecules also in the PR state.…”

Section: Introductionmentioning

confidence: 99%

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Binding pocket dynamics along the recovery stroke of human β-cardiac myosin

2023

Self Cite

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The druggability of small-molecule binding sites can be significantly affected by protein motions and conformational changes. Ligand binding, protein dynamics and protein function have been shown to be closely interconnected in myosins. The breakthrough discovery of omecamtiv mecarbil (OM) has led to an increased interest in small molecules that can target myosin and modulate its function for therapeutic purposes (myosin modulators). In this work, we use a combination of computational methods, including steered molecular dynamics, umbrella sampling and binding pocket tracking tools, to follow the evolution of the OM binding site during the recovery stroke transition of human β-cardiac myosin. We found that steering two internal coordinates of the motor domain can recapture the main features of the transition and in particular the rearrangements of the binding site, which shows significant changes in size, shape and composition. Possible intermediate conformations were also identified, in remarkable agreement with experimental findings. The differences in the binding site properties observed along the transition can be exploited for the future development of conformation-selective myosin modulators.

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“…To decipher how small local differences near the binding site of these force modulators can translate into different energy landscapes and thus different control of actin-binding or Pi release from the motor, all atoms molecular dynamics simulations were performed. Such simulations provide indications for allosteric communication and subdomain reorganization when conformational sub-states are explored 30,35,36,37,38,39,40 . We made a comparative study between three simulations started from S1 bound to Mava, S1 bound to OM and S1 without compound (apo), all bound to Mg.ADP.Pi in the active site (Supplementary Movie 2, 3 and 4).…”

Section: Mobility Of the Primed Lever Arm Greatly Differs When Mava O...mentioning

confidence: 99%

Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction

Auguin,

Robert-Paganin,

Réty

et al. 2023

Preprint

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SummaryInherited cardiomyopathies are amongst the most common cardiac diseases worldwide, leading in the late-stage to heart failure and death. The most promising treatments against these diseases are small-molecules directly modulating the force produced by β-cardiac myosin, the molecular motor driving heart contraction. Two of these molecules that produce antagonistic effects on cardiac contractility have completed clinical phase 3 trials: the activatorOmecamtiv mecarbiland the inhibitorMavacamten. In this work, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All atoms molecular dynamics simulations reveal how these molecules can have antagonistic impact on the allostery of the motor by comparing β-cardiac myosin in the apo form or bound toOmecamtiv mecarbilorMavacamten. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.

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Heart Failure Drug Modifies the Intrinsic Dynamics of the Pre-Power Stroke State of Cardiac Myosin

Cited by 5 publications

References 35 publications

Exploring the Super-Relaxed State of Human Cardiac β-Myosin by Molecular Dynamics Simulations

Exploring the Super-Relaxed State of Human Cardiac β-Myosin by Molecular Dynamics Simulations

Binding pocket dynamics along the recovery stroke of human β-cardiac myosin

Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction

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