MOLECULAR MODELING OF CONFORMATIONS OF NON TRIPLE HELICAL REGIONS OF COLLAGEN

胶原蛋白非三螺旋区域构象的分子建模

• 批准号: 6456775
• 负责人: RAJENDRA S BHATNAGAR
• 金额: $ 27.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6456775
• 关键词: biological products; biomedical resource; carbohydrates; nucleic acids; proteins; technology /technique

We are investigating the conformational tendencies of an imino-poor sequence within the alpha1(I) chain of type I collagen. The sequence GTPGPQGIAGQRGVV, referred to here as P15, shows a tendency to deviate from the triple-helical polyproline-II (ppII) conformation. Our previous studies suggest that this region has a tendency to adopt a conformation in which GIAG is in a beta-bend conformation, flanked by two regions in extended conformations. This is the most likely conformation adopted when bound to integrins. X-ray structures of inhibitors complexed with collagenase suggest that the GIAG region, which is the site of collagenase cleavage, is in an extended conformation when bound to this enzyme. The conformation of regions flanking the GIAG segment during binding to collagenase are unknown. We are thus examining the P15 region's conformational tendencies within collagen, in order to develop a model of how type I collagen interacts with collagenase. The conformational tendencies of collagen, as related to the collagen-collagenase complex, are relevant to the design of collagenase inhibitors for the prevention of tumor metastasis. We are performing molecular dynamics (MD) calculations on the P15 region within the collagen triple-helix. To enhance conformational sampling, we are also incorporating the multicanonical MD (MMD) algorithm into AMBER. Conformations derived from these simulations will be used in docking studies with collagenase. MidasPlus and the facilities of the UCSF Computer Graphics Laboratory have been used for graphical modeling and visualization of the molecular geometry, for preparing preparing starting structures for simulations, for monitoring the simulations.

我们正在研究一种构象倾向 I 型胶原蛋白 alpha1(I) 链内的亚氨基贫乏序列。 序列 GTPGPQGIAGQRGVV（此处称为 P15）显示了 偏离三螺旋聚脯氨酸-II (ppII) 的趋势 构象。 我们之前的研究表明该地区有 倾向于采用 GIAG 处于 β 弯曲的构象 构象，两侧是扩展构象的两个区域。 这 是与整合素结合时最可能采用的构象。 与胶原酶复合的抑制剂的 X 射线结构表明 GIAG 区域是胶原酶裂解的位点，位于 当与该酶结合时，构象扩展。 的构象为 在与胶原酶结合期间，GIAG 片段侧翼的区域是 未知。 因此，我们正在检查 P15 区域的构象 胶原蛋白内的趋势，以开发 I 型胶原蛋白如何变化的模型 胶原蛋白与胶原酶相互作用。 的构象倾向 胶原蛋白，与胶原蛋白-胶原酶复合物有关，是相关的 设计用于预防肿瘤的胶原酶抑制剂 转移。 我们正在执行分子动力学 (MD) 计算 胶原蛋白三螺旋内的 P15 区域。 增强 构象采样，我们还结合了多规范 MD（MMD）算法转化为AMBER。 源自这些的构象 模拟将用于与胶原酶的对接研究。 MidasPlus 和 UCSF 计算机图形实验室的设施 已用于图形建模和可视化 分子几何学，用于制备起始结构 模拟，用于监控模拟。