Nonequilibrium functional dynamics of proteins

生物体中的生物过程发生在由底物（如ATP、离子和配体）的浓度变化引起的固有非平衡条件下。因此，具有缓慢解结合动力学的药物需要较低频率的给药，因此引起较少的副作用。另一个感兴趣的过程是蛋白质自身对配体结合或解结合的反应，这通常相当于变构，即，介导胞内和胞间信号传导的远端结合位点之间的相关结构重排。了解变构通信的路径，动力学和时间尺度允许通过结合抑制这种途径的小分子药物的构建。在研究单元“降低非平衡系统的复杂性”中，本计画将非平衡态与动力学粗粒化方法的形式化描述延伸应用于生物系统，以阐明决定蛋白质-配体时间尺度的分子机制。结合和蛋白质的后续反应。由于构象变化取决于配体的结合模式，并且在配体结合（不结合）期间可能已经发生构象转变，因此这两个主题密切相关。我们将主要追求耗散校正的有针对性的MD和温度提升的Langevin模拟来描述配体与蛋白质的结合或解结合，以及粗粒度的马尔可夫模型来描述蛋白质随后的构象变化。

Biological processes in living organisms occur under inherent nonequilibrium conditions caused by concentration changes of substrates such as ATP, ions and ligands. As one consequence, drugs with slow unbinding kinetics require less frequent dosing and thus cause less side effects. Another process of interest is a protein’s own response to ligand binding or unbinding, which often amounts to allostery, i.e., correlated structural rearrangements between distant binding sites mediating inter- and intracellular signalling. Knowing the paths, dynamics and timescales of allosteric communication allows for the construction of small molecule drugs that inhibit such pathways by binding.Within the Research Unit "Reducing complexity of nonequilibrium systems", this project will extend and apply formal descriptions of nonequilibria and dynamical coarse-graining methods to biological systems to elucidate the molecular mechanisms determining timescales of protein-ligand (un)binding and the following responses of proteins. Since the conformational change depends on the binding mode of the ligand and conformational transitions may already occur during ligand (un)binding, both topics are closely related. We will mainly pursue dissipation-corrected targeted MD and temperature boosted Langevin simulations to describe the binding or unbinding of ligands to proteins, and coarse-grained Markov modeling to describe the subsequent conformational changes of proteins.