Folding and Structural Transitions in Small Proteins

描述（由申请人提供）：该提案代表了对蛋白质折叠模拟的广义系综方法的应用的扩展研究。这是PI在过去几年中所做工作的延续。PI打算将其a）组开发的新技术应用于研究折叠转变以及少数精心选择的仅具有α-螺旋或β-折叠作为二级结构元件的蛋白质中二级和三级结构形成之间的关系。将考虑以下肽：（36个残基，全螺旋），Beta 3s（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），和Anthopleurin A（49个残基，全β-折叠）; B）研究低能结构的系综，蛋白L的62个残基IgG结合结构域和链球菌蛋白G的56个残基区段B1的能量景观和折叠。这两种小的快速折叠蛋白质具有螺旋和β折叠，因此允许人们对小蛋白质的复杂实例的上述研究的结果进行探索; c）并在一些蛋白质片段中研究从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，这种研究的热力学折叠和其他结构转变的蛋白质将导致一个更好的理解折叠的机制。这将使人们能够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.