利用可极化分子力场研究天然无序蛋白质的构象系综与自组装

The conformational dynamics and self-assembly of intrinsically disordered proteins involve significant changes in the electrostatic environment of amino acids, such that conventional fixed-charge, additive force fields have their intrinsic difficulties and accuracy limits in modeling disordered proteins. We propose using polarizable force fields, which in principle would have higher accuracy, to study the conformational ensembles and self-assembly of intrinsically disordered proteins. By utilizing the acceleration of polarizable simulations brought by GPUs, we will present a large-scale, systematical study of intrinsically disordered proteins using microsecond all-atom explicit solvent molecular dynamics simulations with the polarizable Drude-2013 protein force field. We will assess the accuracy of current polarizable protein force fields in modeling intrinsically disordered proteins, and investigate the effect of chemical denaturants such as urea and guanidinium chloride on their conformational dynamics. We will also study some model disordered protein systems with quantum chemistry calculations, molecular mechanics calculations and molecular dynamics simulations, in order to investigate the dynamics and kinetics of peptide aggregation and assembly. Our study will help understand the molecular mechanism of amyloid formation and accumulation, and help develop chemical, biological or physical therapeutic solutions to slow down or treat amyloid diseases.

天然无序蛋白质的构象动力学和自组装过程涉及氨基酸在不同静电微环境下的转换，因此传统的固定电荷力场模型在模拟无序蛋白质时有其固有的困难与精度极限。本项目将使用原则上精度更高的可极化分子力场来研究天然无序蛋白质的构象与自组装。利用图形处理器（GPU）对可极化模拟带来的硬件加速，我们将使用Drude-2013可极化蛋白质力场对天然无序蛋白质体系进行大规模、系统性、微秒时间尺度的全原子显式溶剂分子动力学模拟。由此我们将评估现有可极化蛋白质力场在模拟无序蛋白质时的精度，并探究尿素、盐酸胍等化学变性剂对无序蛋白质的构象动力学的影响。本项目还将通过对无序蛋白质模型系统的量子化学计算、分子力场计算和可极化力场分子动力学模拟，研究多肽的聚合和自组装过程，探索天然无序蛋白质淀粉样变的分子机理，为寻找利用化学、生物和物理手段来减缓和治疗老年痴呆等疾病的方案提供帮助。

课题围绕Drude可极化力场，重点研究以天然无序蛋白为代表的蛋白体系的构象动力学与自组装。我们使用Drude-2013可极化蛋白质力场以及新开发的Drude-2019蛋白质力场，在可极化力场的评估和优化方面取得了一系列进展，在模拟方法如LJ-PME算法上做了一系列探索。我们还通过对一系列生物学和化学重要体系的基于可极化力场的动力学研究，增强了对于无序蛋白与短肽在溶液相及界面上的聚集和自组装过程的理解，展现了显式处理电子极化效应在刻画蛋白结构和动力学上的优势，凸显了更精确的物理模型对于复杂体系分子模拟的重要性。在项目执行期间受项目资助发表10篇研究论文于Science, Cell Research等高水平SCI期刊。

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