Computational Analysis for Amyloid Formation

朊病毒病的发病机制尚不清楚。在这项研究中，基于分子动力学模拟，我们研究了朊病毒蛋白（PrP）的结构不稳定性，这促进了部分螺旋到折叠构象转换。PrP的这种不稳定性促进活性中间体前体（PrP*）的形成，其可导致正常朊病毒蛋白（PrPC）构象转化为致病性同种型（PrPSc）。我们提出了一种新的方法来系统地构建一个自由能景观映射大量的蛋白质结构数据到一个约简空间，根据其二级结构，命名为二级结构主成分分析（SSPCA）。PrP* 的确定存在在自由能景观中得到了证实。PrP* 与其正常型的存在比估计为0.07。SSPCA方法具有很大的潜力，以解决各种挑战，在研究高度灵活的分子系统，比PrPs。

The developing mechanism of prion diseases has remained unclear. In this study, based on molecular dynamics simulations, we investigated the structural instability in prion protein (PrP), which promotes a partial helix-to-sheet conformational conversion. This instability of PrP facilitates the formation of active intermediate precursors (PrP*) that can lead to the conformational conversion of the normal prion protein (PrPC) to the pathogenic isoform (PrPSc). We propose a novel method to systematically construct a free-energy landscape by mapping massive protein structural data into a reduced space according to their secondary structures, named secondary structure principal component analysis (SSPCA). The definite existence of PrP* was confirmed in the free-energy landscape. The existence ratio in number of PrP* to its normal form was estimated to be 0.07. The SSPCA method has great potential to solve various challenges in studying highly flexible molecular systems, other than PrPs.