MOLECULAR MODELING OF CONFORMATIONS OF NON TRIPLE HELICAL REGIONS OF COLLAGEN

我们正在研究一种 I型胶原α 1（I）链内的亚氨基贫乏序列。 序列GTPGPQGIAGQRGVV，在此称为P15，显示了一个 偏离三螺旋聚脯氨酸-II（ppII）的趋势 构象 我们以前的研究表明，这个地区有一个 倾向于采用GIAG处于β-弯曲的构象 构象，两侧是延伸构象中的两个区域。 这 是与整联蛋白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， 作为胶原酶切割位点的GIAG区位于 当与这种酶结合时， 的构象 在与胶原酶结合期间，GIAG区段侧翼的区域是 未知 因此，我们正在研究P15区域的构象 胶原蛋白内的倾向，以建立一个模型，如何I型 胶原与胶原酶相互作用。 的构象趋势 与胶原蛋白-胶原酶复合物相关的胶原蛋白是相关的 涉及用于预防肿瘤的胶原酶抑制剂的设计 转移 我们正在进行分子动力学（MD）计算， 胶原蛋白三螺旋内的P15区域。 加强 构象采样，我们也将多规范 MD（MMD）算法转化为AMBER。 从这些衍生的构象 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 已被用于图形建模和可视化的 分子几何学，用于制备 模拟，用于监控模拟。

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.