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Inherited cardiomyopathies are 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. Omecamtiv mecarbil and Mavacamten are two such molecules that completed phase 3 clinical trials, and the inhibitor Mavacamten is now approved by the FDA. In contrast to Mavacamten, Omecamtiv mecarbil acts as an activator of cardiac contractility. Here, 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-atom molecular dynamics simulations reveal how these molecules produce distinct effects in motor allostery thus impacting force production in opposite way. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine. Omecamtiv mecarbil and Mavacamten are small molecules directly modulating the force produced by β-cardiac myosin. In this work, the authors describe how the modulators Omecamtiv mecarbil and Mavacamten can have opposite effects on cardiac myosin force production despite occupying the same pocket. [ABSTRACT FROM AUTHOR]

Aquaporins (AQPs) constitute a wide family of water channels implicated in all kind of physiological processes. Zinc is the second most abundant trace element in the human body and a few studies have highlighted regulation of AQP0 and AQP4 by zinc. In the present work, we addressed the putative regulation of AQPs by zinc cations in silico through molecular dynamics simulations of human AQP0, AQP2, AQP4, and AQP5. Our results align with other scales of study and several in vitro techniques, hence strengthening the reliability of this regulation by zinc. We also described two distinct putative molecular mechanisms associated with the increase or decrease in AQPs' water permeability after zinc binding. In association with other studies, our work will help deciphering the interaction networks existing between zinc and channel proteins. [ABSTRACT FROM AUTHOR]

[Display omitted] • The G4 helicase BsPif1 possesses independent binding sites for both ssDNA and G4. • ssDNA translocation driven by ATP hydrolysis, exerts a pulling force on G4 unwinding. • There is a distinct G4 binding region that play a critical role in G4 unwinding. • A novel theoretical framework for the G4 development mechanism within Pif1 helicases. The G-quadruplex (G4) is a distinct geometric and electrophysical structure compared to classical double-stranded DNA, and its stability can impede essential cellular processes such as replication, transcription, and translation. This study focuses on the Bs Pif1 helicase, revealing its ability to bind independently to both single-stranded DNA (ssDNA) and G4 structures. The unfolding activity of Bs Pif1 on G4 relies on the presence of a single tail chain, and the covalent continuity between the single tail chain and the G4′s main chain is necessary for efficient G4 unwinding. This suggests that ATP hydrolysis-driven ssDNA translocation exerts a pull force on G4 unwinding. Molecular dynamics simulations identified a specific region within Bs Pif1 that contains five crucial amino acid sites responsible for G4 binding and unwinding. A "molecular wire stripper" model is proposed to explain Bs Pif1′s mechanism of G4 unwinding. These findings provide a new theoretical foundation for further exploration of the G4 development mechanism in Pif1 family helicases. [ABSTRACT FROM AUTHOR]