Kinetics and Morphology of Self-Associating Beta-Sheet Peptides

自缔合β片肽的动力学和形态

• 批准号: 0330537
• 负责人: Regina Murphy
• 金额: --
• 依托单位: University of Wisconsin-Madison
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-11-01 至 2008-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0330537&HistoricalAwards=false
• 关键词: Kinetics; Morphology; Self; Associating; Beta

0330537MurphyMany peptides and proteins spontaneously self-associate into large aggregates of cross beta-sheet structure and fibrillar morphology, which may be toxic to a wide number of cell types, due simply to their morphology and not to their specific sequence. Thus, elucidation of the factors that control peptide self-association into fibrillar aggregates is needed to understand mechanisms of disease, to develop therapeutic strategies for these diseases, and to design efficient processes for protein manufacture and formulation. The objectives of this research are: (1) to develop a detailed mathematical model of the kinetics of assembly of fibril-forming peptides and proteins, (2) to design and synthesize fibril-forming peptides in which morphology is controlled by judicious balancing of backbone hydrogen-bonding and side chain-side chain interactions, and (3) to develop rules to predict whether pairs of interacting peptides will have greater or lesser aggregation propensity than each peptide in isolation. Three model systems will be used in pursuing these objectives: (1) Insulin and insulin analogs, (2) Apomyoglobin truncation mutants, and (3) Polyglutamine and other expanded-domain peptides. Kinetics of assembly are monitored using several complementary experimental techniques: static and dynamic light scattering,

许多多肽和蛋白质自发地自结合成大的交叉β -片结构和纤维状形态的聚集体，这可能对许多细胞类型有毒，仅仅是因为它们的形态，而不是它们的特定序列。因此，需要阐明控制肽自结合成纤维聚集体的因素，以了解疾病的机制，为这些疾病制定治疗策略，并设计有效的蛋白质制造和配方过程。本研究的目标是：(1)建立纤维形成肽和蛋白质组装动力学的详细数学模型；(2)设计和合成纤维形成肽，其形态由主氢键和侧链-侧链相互作用的合理平衡控制；(3)制定规则来预测相互作用的肽对是否比单独的每个肽具有更大或更小的聚集倾向。三个模型系统将用于实现这些目标：(1)胰岛素和胰岛素类似物，(2)无肌红蛋白截断突变体，(3)聚谷氨酰胺和其他扩展结构域肽。装配动力学使用几种互补的实验技术进行监测：静态和动态光散射，