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• W3036253146 abstract "ABSTRACT Prevalent resistance to inhibitors that target the influenza A M2 proton channel has necessitated a continued drug design effort, supported by a sustained study of the mechanism of channel function and inhibition. Recent high-resolution X-ray crystal structures present the first opportunity to see how the adamantyl-amine class of inhibitors bind to M2 and disrupt and interact with the channel’s water network, providing insight into the critical properties that enable their effective inhibition in wildtype M2. In this work, we test the hypothesis that these drugs act primarily as mechanism-based inhibitors by comparing hydrated excess proton stabilization during proton transport in M2 with the interactions revealed in the crystal structures, using the Multiscale Reactive Molecular Dynamics (MS-RMD) methodology. MS-RMD, unlike classical molecular dynamics, models the hydrated proton (hydronium-like cation) as a dynamic excess charge defect and allows bonds to break and form, capturing the intricate interactions between the hydrated excess proton, protein atoms, and water. Through this, we show that the ammonium group of the inhibitors is effectively positioned to take advantage of the channel’s natural ability to stabilize an excess protonic charge and is thus acting as a hydronium-mimic. Additionally, we show that the channel is especially stable in the drug binding region, highlighting the importance of this property for binding the adamantane group. Finally, we characterize an additional hinge point near Val27, which dynamically responds to charge and inhibitor binding. Altogether, this work further illuminates a dynamic understanding of the mechanism of drug inhibition in M2, grounded in the fundamental properties that enable the channel to transport and stabilize excess protons, with critical implications for future drug design efforts. TOC Graphic" @default.
• W3036253146 created "2020-06-25" @default.
• W3036253146 creator A5001612107 @default.
• W3036253146 creator A5008991090 @default.
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• W3036253146 date "2020-06-20" @default.
• W3036253146 modified "2023-09-27" @default.
• W3036253146 title "Influenza A M2 Inhibitor Binding Understood through Mechanisms of Excess Proton Stabilization and Channel Dynamics" @default.
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• W3036253146 doi "https://doi.org/10.1101/2020.06.19.162248" @default.
• W3036253146 hasPublicationYear "2020" @default.
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