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Molecular Dynamics Simulations Reveal the Mechanisms of Allosteric Activation of Hsp90 by Designed Ligands

机译：分子动力学模拟通过设计配体揭示了HSP90的变构激活的机制

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Controlling biochemical pathways through chemically designed modulators may provide novel opportunities to develop therapeutic drugs and chemical tools. The underlying challenge is to design new molecular entities able to act as allosteric chemical switches that selectively turn on/off functions by modulating the conformational dynamics of their target protein. We examine the origins of the stimulation of ATPase and closure kinetics in the molecular chaperone Hsp90 by allosteric modulators through atomistic molecular dynamics (MD) simulations and analysis of protein-ligand interactions. In particular, we focus on the cross-talk between allosteric ligands and protein conformations and its effect on the dynamic properties of the chaperone's active state. We examine the impact of different allosteric modulators on the stability, structural and internal dynamics properties of Hsp90 closed state. A critical aspect of this study is the development of a quantitative model that correlates Hsp90 activation to the presence of a certain compound, making use of information on the dynamic adaptation of protein conformations to the presence of the ligand, which allows to capture conformational states relevant in the activation process. We discuss the implications of considering the conformational dialogue between allosteric ligands and protein conformations for the design of new functional modulators.
机译：通过化学设计的调节器控制生化途径可以提供开发治疗药物和化学工具的新机遇。潜在的挑战是设计能够充当颠覆化学交换机的新分子实体，通过调节其靶蛋白的构象动态来选择性地打开/关闭功能。通过原子分子动力学（MD）模拟和蛋白质配体相互作用分析，通过构复调制器来检查分子伴侣HSP90中ATP酶HSP90刺激的起源和闭合动力学。特别是，我们专注于构建性配体和蛋白质构象之间的串扰及其对伴随伴侣的活跃状态的动态性质的影响。我们研究了不同变构调制器对HSP90关闭状态的稳定性，结构和内部动力学性质的影响。该研究的一个关键方面是发展与某种化合物的存在相关的定量模型，其与某种化合物的存在相关，利用关于蛋白质构象的动态适应与配体的存在的信息，这允许捕获相关状态在激活过程中。我们讨论了考虑构象性与蛋白质构象之间的构象对话的含义，用于设计新的功能调节剂的设计。

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