COMPUTATIONAL STUDIES OF PRION PROTEIN STRUCTURE

我们假设朊病毒疾病是由于 PrPc的构象和低聚状态，使得PrPc PrPsc 低聚物。 PrPc的物理化学性质使其 很难进行实验性生物物理研究来确定 这种蛋白质的结构。 我们提出了一系列的理论研究 来模拟PrP可能的构象。 新方法 二级结构预测将应用于已知的家族 PrP序列。 启发式模型的二级结构包装将 用来提出合理的三级结构。 肽已经 基于PrP中可能的二级结构的区域设计。 我们的同事在本计划项目赠款中的最新实验 表明这些肽在某些条件下可以采用α-螺旋结构 在其他条件下，β-结构。 其实有些 这些肽中的一种能够形成淀粉样蛋白。 我们计划使用 分子动力学计算来模拟构象行为 这些肽。 模拟将在水中进行， 可以模拟膜环境的各种混合溶剂。 的 这些研究的结果应该表明，突变可能会影响 肽的构象偏好以及可能的构象偏好 完整蛋白质的偏好。 肽聚集的模型将 可以从两个或多个肽的分子动力学模拟中开发。 同样，与Prusiner的实验结果密切相关， 组将是至关重要的计算工作的进展。 从肽模拟的结果来看， 完整PrP分子的有用模型。 我们预计 将开发替代模型，并进行诱变实验。 旨在帮助在替代模型之间进行排序， 诱变实验将被设计成帮助在替代方案之间进行排序。 模型 插入和缺失突变以及引入 新的二硫桥可以提供结构信息， 确认或反驳替代模型结构。

We hypothesize that prion diseases are a result of changes in the conformation and oligomerization state of PrPc, such that PrPc PrPsc Oligomer. The physical-chemical properties of PrPc have made it difficult to conduct experimental biophysical studies to determine the structure of this protein. We propose a series of theoretical studies to model the structure of the possible conformers of PrP. New methods for secondary structure prediction will be applied to the family of known PrP sequences. Heuristic models for secondary structure packing will be used to propose plausible tertiary structures. Peptides have been designed based on the regions of likely secondary structure in PrP. Recent experiments by our colleagues in this Program Project Grants suggest that these peptides can adopt an a-helical structure under some conditions and a beta-structure under other conditions. In fact, some of these peptides are capable of forming amyloid. We plan to use molecular dynamics calculations to stimulate the conformational behavior of these peptides. Simulations will be carried out in water and a variety of mixed solvents that could mimic the membrane environment. The results of these studies should suggest mutations that could effect the conformational preference of the peptide and perhaps the conformational preferences of the intact protein. Models of peptide aggregation will be developed from molecular dynamics simulations of two or more peptides. Again, a close correlation with experimental results from the Prusiner group will be critical to the progress of the computational effort. From the results of the peptide simulation, it may be possible to develop a useful model of the intact PrP molecule. We anticipate that alternative models will be developed and mutagenesis experiments will be designed to help sort between alternative models will be developed and mutagenesis experiments will be designed to help sort between alternative models. Insertion and deletion mutations as well as the introduction of new disulfide bridges could provide structural information that would confirm or refute the alternative model structures.