MOLECULAR MODELING OF CONFORMATIONS OF NON TRIPLE HELICAL REGIONS OF COLLAGEN

我们正在研究一个分子的构象趋势 I型胶原蛋白的α1(I)链中缺乏亚氨基的序列。 序列GTPGPQGIAGQRGVV，这里称为P15，显示了 偏离三螺旋多聚Pro-II(PpII)的倾向 构象。我们之前的研究表明，这个地区有一个 倾向于采用GIAG处于Beta弯的构象 构象，两侧是延伸构象中的两个区域。这 是与整合素结合时最有可能采用的构象。 与胶原酶络合的抑制剂的X射线结构表明 胶原酶的裂解部位GIAG区域处于 当与这种酶结合时，延长的构象。的构象 在与胶原酶结合期间，GIAG片段两侧的区域为 未知。因此，我们正在研究P15区域的构象 胶原蛋白中的趋势，以开发I型胶原如何 胶原蛋白与胶原酶相互作用。分子的构象趋势 与胶原蛋白-胶原酶复合体相关的胶原蛋白 胶原酶抑制剂用于肿瘤预防的设计 转移。我们正在进行分子动力学(MD)计算 胶原蛋白三螺旋结构中的P15区域。为了增强 构象采样，我们还结合了多克隆 MD(MMD)算法转化为琥珀。从这些衍生出来的构象 模拟将用于胶原酶的对接研究。 MidasPlus与加州大学旧金山分校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，用于制备制备起始结构 模拟，用于监视模拟。

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.