朊蛋白的误折叠会导致多种中枢神经系统疾病。由于实验手段的不足，分子动力学模拟已成为研究朊蛋白误折叠机制的主要手段。但受到模拟时间及分子力场精度的限制（缺乏静电极化效应且具有不同程度的二级结构倾向性），朊蛋白误折叠机制的理论研究仍面临很多困难。申请人在博士期间发展了包含静电极化效应和采用二维傅立叶展开表达主链二面角势能项的分子力场（AMBER2DP），提高了分子力场的精度。本项目将在前期工作的基础上，采用多尺度动力学模拟来研究朊蛋白的误折叠机制，主要开展以下三方面工作：1）基于AMBER2DP力场，采用全原子分子动力学模拟研究朊蛋白误折叠初期各个结构域的构象变化，解决不同研究组对此的争议。2）研究H1结构域、关键残基对朊蛋白误折叠的影响。3）结合粗粒化模型和基于AMBER2DP的全原子动力学模拟研究朊蛋白的误折叠路径并预测其致病构象的结构。本项目有望为朊蛋白的误折叠机制提供全面且深入的解释。

The misfolding of prion protein can lead to a vast of neurodegenerative diseases. Due to the deficiency of experiments in spatial resolution, molecular dynamics simulation has become an important method to investigate the mechanism of its conformational change and misfolding. However, it still faces some problems due to the limit of simulation time and the accuracy of current force fields (the lack of electrostatic polarization effect and unbalanced secondary structure distribution). In our previous work, we proposed AMBER2DP force field by incorporating polarization effect and utilizing a set of two-dimensional Fourier series for main chain torsions, which has been proved to improve the accuracy of current force field. This project aims to utilize multiscale molecular dynamics simulations to investigate the mechanism of the misfolding of prion protein based on our preliminary work, mainly in the following three aspects: 1) To investigate the conformational change of different domains of prion protein utilizing all-atom molecular dynamics simulation with AMBER2DP force field, solving the conflicts among different groups. 2) To study the function of H1 domain and some key residues for the protein misfolding. 3) To describe the misfolding pathway of prion protein and to predict the possible structure of misfolded prion protein with coarse grained and all atom molecular dynamics simulaions. This work can provide a comprehensive and deepgoing knowledge of the misfolding of prion protein.