Protein Structure, Stability, and Amyloid Formation

研究的重点是蛋白质结构及其相互作用的原理，以将蛋白质结构和功能联系起来。我们已经确定蛋白质折叠和蛋白质-蛋白质结合是相似的过程，具有相似的基本原理。两者都涉及(内部 或分子间)识别。这一原理对在细胞途径中相互作用的蛋白质有影响，无论是链式连接的还是独立的实体。这与连接或拆分链的实验是一致的，仍然获得了相似的结构。它提出了在蛋白质折叠方案中降低计算复杂性的方法，以及功能保守区域对于保持结构完整性也是关键的；它使蛋白质构象对大多数突变的惊人免疫力合理化。它使我们能够设计出一种方法，将蛋白质切割成与实验数据一致的构象稳定或波动的“积木”，并将其用于实现这些目标。蛋白质的结构及其稳定性直接关系到蛋白质的功能。因此，我们探索了这些因素的主要决定因素，重点是中嗜冷菌、嗜热菌和中嗜冷菌，并延伸到喜欢寒冷的嗜冷菌。 错误折叠的蛋白质出现故障。淀粉样蛋白的形成既耐人寻味，又具有极其重要的实际应用。我们既研究了肽模型系统，也研究了完整的蛋白质，并提供了很好的实验数据。计算研究可以探索这些过程的细节。对于模型多肽系统，我们的目标是找到种子的最小尺寸、原纤维的构象和种子生长的机制。这些多肽来自淀粉样蛋白，并被证明形成了原纤维。对于淀粉样蛋白，我们重点研究天然蛋白经历这些构象变化的机制。分子动力学可以独一无二地帮助提供详细的信息，这些信息可以用于药物设计和潜在的早期检测分子探针。我们专注于一些分子，特别是阿尔茨海默氏症A-β和胰岛淀粉样多肽。我们的模拟结果与实验结果一致。特别是，我们提出的A-β模型与最近的基于固体核磁共振的模型惊人地一致。这些研究还补充了对β-结构家族中残基保守的数据库分析，以了解β-折叠稳定性的起源。

Research focuses on the principles of protein structures and their associations, to relate protein structure and function. We have established that protein folding and protein-protein association are similar processes with similar underlying principles. Both involve (intra- or inter-) molecular recognition. Such a principle has implications for proteins which interact in cellular pathways, whether chain-linked or separate entities. It is consistent with experiments linking chains or splitting them, still obtaining similar structures. It suggests ways to reduce the computational complexity in protein folding schemes and that functionally conserved regions are also critical to maintain structural integrity; It rationallizes the striking immunity of protein conformations to most mutations. It has enabled us to devise a method to cut the protein into its conformationally stable or fluctuating `building blocks' consistent with experimental data, and to utilize it toward these goals. Protein structure and its stability directly relate to protein function. We consequently probe the major determinants of these, focusing on mesophiles, thermophiles versus mesophiles, and extending to the cold-loving psychrophiles. Misfolded proteins malfunction. Amyloid formation is both intriguing and has extremely important practical applications. We study both peptide model systems and entire proteins with well documented experimental data. Computational studies can explore the details of the processes. For the model peptide systems our goals are to find the minimal seed size, the conformation of the protofibril and the mechanism of seed growth. The peptides are derived from amyloidogenic proteins, and shown to form protofibrils. For the amyloidogenic proteins, we focus on the mechanisms through which native proteins undergo these conformational changes. Molecular dynamics can uniquely aid in supplying detailed information which can be used for drug design and in potential molecular probes for early detection. We focus on a number of molecules, particularly the Alzheimer's A-beta and the Islet amyloid polypeptide. Our simulations have obtained results consistent with experiment. In particular, our proposed model for the A-beta is in striking agreement with recent solid state NMR-based model. These studies are supplemented by database analysis of residue conservation in families of beta-structures, to understand the origin of beta-sheet stability.