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中广义集成方法应用的扩展研究。这是PI在过去几年所做工作的延续。PI打算将在他的小组a)中开发的新技术应用于研究折叠转变和二级和三级结构形成之间的关系，在一些精心挑选的蛋白质中，这些蛋白质要么只有-螺旋，要么只有-薄片作为二级结构元素。以下肽将被考虑：HP-36（36个残基，全螺旋），Beta3s(20个残基，全β -sheet)，葡萄球菌蛋白A的B结构域（45个残基，全螺旋）和anthpleurin A(49个残基，全β -sheet)；b)研究蛋白质L的62个残基igg结合域和链球菌蛋白g的56个残基B1段的低能结构、能量景观和折叠的集合。这两个快速折叠的小蛋白质既有螺旋结构，也有β -片，因此可以将上述研究结果用于小蛋白质的复杂例子中；C)和研究一些蛋白质片段，从螺旋到薄片的转变，这被认为是导致各种神经退行性疾病爆发的原因。希望对蛋白质中折叠的热力学和其他结构转变的研究将有助于提高对折叠机制的理解。这将使人们更好地理解与某些蛋白质功能障碍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.