朊病毒蛋白构象发生改变，形成beta片含量较大的病变朊病毒蛋白被认为是引发朊病毒疾病的重要原因。大量的实验和理论研究证实，在朊蛋白构象改变过程中，螺旋H１稳定，H２和H３发生部分解旋，beta片S１和S２略有增长，但beta片含量大幅增加的机制仍然不清楚。本课题组在前期模拟中结合常温，高温分子动力学模拟和模拟退火首次观察到一个从未被报道的，稳定存在的新beta片S３，并在此基础上与N端残基118-122一起模拟出反平行4beta片层。因此，我们提出原先被人们忽视的，在三维结构中呈无序结构的N端区域残基23-116形成多个beta-hairpin，并二聚成beta-桶状结构是朊病毒蛋白构象改变的新机制。我们拟利用在前期模拟中研发的新分子极化力场PSBC，结合多种分子模拟手段对这段蛋白序列在酸性条件下的折叠进行系统的研究，进而预测整个朊病毒蛋白(23-228)的溶液三维结构和它的自组装机制。

Conformational conversion of normal cellular prion protein to its misfolded, beta-rich, and oligomeric counterpart PrPsc is believed to be the key event for the development of prion diseases. Extensive studies have been conducted but the underlying mechanism for the substantial increase of beta composition during the conformational conversion still remains elusive. Based on the formation of a new beta-sheet, namely S3 after the partial denaturation of H2 and H3 helix, we obtained a four-strand antiparallel beta-sheet in preliminary simulations. Therefore, we propose to target the previously ignored and the structurally disordered N-terminal region (res 23-116), which may have a high propensity to form beta-hairpins and then beta-barrel like structure by dimerization. In this study, we will apply the newly proposed and developed polarizable structure-specific backbone charge (PSBC) to carry out systematic folding simulations of the N-terminal part by combining MD simulations under different temperatures and simulated annealing to predict the 3D structure of Prpsc and then explore the mechanism of Prpsc assembly. This research aims to provide new ideas and new targets on the prevention and control of prion diseases and the diseases caused by protein misfolding and aggregation such as Parkinson's and alzheimer's disease.