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• W2974664089 endingPage "6381" @default.
• W2974664089 startingPage "6368" @default.
• W2974664089 abstract "The molecular chaperone HSP90 oversees the functional activation of a large number of client proteins. Because of its role in multiple pathways linked to cancer and neurodegeneration, drug discovery targeting HSP90 has been actively pursued. Yet, a number of inhibitors failed to meet expectations due to induced toxicity problems. In this context, allosteric perturbation has emerged as an alternative strategy for the pharmacological modulation of HSP90 functions. Specifically, novel allosteric stimulators showed the interesting capability of accelerating HSP90 closure dynamics and ATPase activities while inducing tumor cell death. Here, we gain atomistic insight into the mechanisms of allosteric ligand recognition and their consequences on the functional dynamics of HSP90, starting from the fully unbound state. We integrate advanced computational sampling methods based on FunnelMetadynamics, with the analysis of internal dynamics of the structural ensembles visited during the simulations. We observe several binding/unbinding events, and from these, we derive an accurate estimation of the absolute binding free energy. Importantly, we show that different binding poses induce different dynamics states. Our work for the first time explicitly correlates HSP90 responses to binding/unbinding of an allosteric ligand to the modulation of functionally oriented protein motions." @default.
• W2974664089 created "2019-09-26" @default.
• W2974664089 creator A5005907422 @default.
• W2974664089 creator A5017201543 @default.
• W2974664089 creator A5026034661 @default.
• W2974664089 creator A5046491394 @default.
• W2974664089 creator A5080776540 @default.
• W2974664089 date "2019-09-20" @default.
• W2974664089 modified "2023-10-17" @default.
• W2974664089 title "Ligand Binding, Unbinding, and Allosteric Effects: Deciphering Small-Molecule Modulation of HSP90" @default.
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