Nonequilibrium functional dynamics of proteins

生物体的生物过程是在ATP、离子和配体等底物的浓度变化所引起的固有不平衡条件下进行的。其结果之一是，具有缓慢解结合动力学的药物需要较少的频繁给药，从而引起较少的副作用。另一个令人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，即介导细胞间和细胞内信号传导的远端结合位点之间的相关结构重排。了解变构通讯的途径、动力学和时间尺度，可以构建通过结合抑制这种途径的小分子药物。在“降低非平衡系统的复杂性”研究单元内，该项目将扩展并应用非平衡和动态粗粒度方法的正式描述到生物系统中，以阐明决定蛋白质-配体（非）结合时间尺度的分子机制以及蛋白质的后续反应。由于构象变化取决于配体的结合方式，而构象转变可能已经在配体（非）结合过程中发生，因此这两个主题密切相关。我们将主要研究耗散校正的靶向MD和温度增强的朗格万模拟，以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，以描述蛋白质的后续构象变化。

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.