Folding and Structural Transitions in Small Proteins

描述(由申请人提供)：这项提案代表了对广义系综方法在蛋白质折叠模拟中的应用的扩展调查。这是过去几年国际和平研究所所做工作的延续。PI打算将他的小组a)中开发的新技术应用于研究折叠转变以及在几个精心选择的蛋白质中二级结构和三级结构形成之间的关系，这些蛋白质只有α-螺旋或β-折叠作为二级结构元素。将考虑下列多肽：HP-36(36个残基，全螺旋)，Beta3S(20个残基，全β-折叠)，葡萄球菌蛋白A的B结构域(45个残基，全螺旋)，以及Anthopleurin A(49个残基，全β-折叠)；B)研究L蛋白的62个残基免疫球蛋白结合结构域和链球菌蛋白G的56个残基片段B1的低能结构、能量格局和折叠，这两个小的快速折叠蛋白既有螺旋又有β-折叠，从而使人们能够探索上述研究结果以寻找复杂的小蛋白例子；c)以及研究一些蛋白质片段，即从α-螺旋到β-折叠的转变，这被认为是导致各种神经退行性疾病爆发的原因。人们希望，对蛋白质折叠和其他结构转变的热力学的研究将有助于更好地理解折叠的机制。这将使人们更好地了解与某些蛋白质故障相关的各种疾病的爆发，并可能导致更有效的药物设计方法。

DESCRIPTION (provided by applicant): This proposal represents an extended investigation into the application of the generalized-ensemble approach for protein-folding simulations. It is a continuation of the work that the PI did over the last few years. The PI intends to apply the novel techniques that were developed in his group a) to a study of folding transitions and the relation between secondary and tertiary structure formation in a few carefully selected proteins that have either only alpha-helices or beta-sheets as secondary structure elements. The following peptides will be considered: HP-36 (36 residues, all-helical), Beta3s (20 residues, all-beta-sheet), the B domain of staphylococcal protein A (45 residues, all-helical), and Anthopleurin A (49 residues, all-beta-sheet); b) to study the ensemble of low-energy structures, energy landscape and folding of the 62-residue IgG-binding domain of protein L and the 56-residue segment B1 of streptococcal protein G. These two small fast-folding proteins have both helix and beta-sheets and therefore allow one to probe results of the above investigation for complex examples of small proteins; c) and to research in some protein fragments, the transition from an alpha-helix to a beta-sheet, that is thought to be responsible for the outbreak of various neurodegenerative diseases. It is hoped that such research of the thermodynamic of folding and other structural transitions in proteins will lead to an improved understanding of the mechanism of folding. This would allow one to understand better the outbreak of various diseases associated with the malfunction of certain proteins and could lead to more efficient ways of drug design.