MOLECULAR BASIS OF COLLAGEN REACTIVITY

胶原蛋白参与了许多相互作用，这些相互作用有助于 所有结缔组织的形态、功能、生理和病理生物学。 胶原蛋白相互作用障碍在病理生物学中的作用 口腔组织、骨骼和心血管系统的变化， 如果这些相互作用在胚胎阶段受到干扰， 可能会出现发育障碍。为了了解生理学 以及胶原蛋白的病理生物学，有必要阐明其分子 胶原蛋白反应的基础。我们在这项建议中的目标是 阐明反应部位的性质和物理化学因素 来控制它们的反应能力。胶原蛋白的活性部位是 轴向分布在三股螺旋上。我们的假设是 这些部位的生物学特异性取决于不同的和特异性的 为相互作用的物种提供了分子视角。一种同质的 沿着三螺旋的整个长度延伸的构象将 排除了这种特殊性。为了让反应性位点表达 在配体的方法上的特定分子透视，这些区域 必须至少暂时脱离构象 存在于分子的其余部分。这一点得到了观察的支持 胶原蛋白的某些相互作用是通过变性促进的 条件。根据我们的假设，特定基因的表达 反应性不仅取决于特定的序列标记，而且还取决于 稳定三螺旋的链间相互作用的差异 在反应部位和邻近的非反应区域，因为这将 促进向 正在接近莱兰德。我们进一步提出富含亚米诺的结构 序列支持三螺旋构象的程度是大多数 常用的实验技术揭示了，相对 限制在这种构象中的亚米诺稀疏反应序列 对胶原蛋白上不同部位的特异性反应。我们计划 通过研究胶原蛋白功能的这一重要基础 从结构和反应区分离的序列的构象 胶原蛋白，通过使用合成多肽模型进行实验， 并利用能量和分子力学的理论技术， 构象的动力学计算和模拟。分子内 结构和反应性稳定性中的相互作用 构象将通过实验和理论来确定 程序。

The collagens are involved in numerous interactions which contribute to the form, function, physiology and pathobiology and of all connective tissues. Disturbances in the interactions of collagen contribute to pathobiological changes in oral tissues, in the skeleton and in the cardiovascular system, and if these interactions are perturbed during embryonic stages, developmental disorders can arise. In order to understand the physiology and pathobiology of collagen it is necessary to elucidate the molecular basis of the reactions of collagen. Our objective in this proposal is to elucidate the nature of the reactive sites and the physico-chemical factors that govern their reactivity. The reactive sites of collagen are distributed axially on the triple helix. Our hypothesis is that the biological specificity of these sites depends on distinct and specific molecular perspectives offered to the interacting species. A homogenous conformation extending along the entire length of the triple helix would preclude such specificity. In order for the reactive sites to express specific molecular perspectives at the approach of a ligand, these regions of the triple helix must depart at least transiently from the conformation extant in the rest of the molecule. This is supported by the observation that certain interactions of collagen are promoted by denaturing conditions. According to our hypothesis, the expression of specific reactivity depends not only on specific sequence markers, but also on differences in the inter-chain interactions that stabilize the triple helix in the reactive sites and adjacent non-reacting regions since that would facilitate the presentation of a distinct molecular perspective to an approaching ligand. We propose further that imino-rich structural sequences support the triple helical conformation to the extent that most commonly used experimental techniques reveal, and that relatively imino-sparse reactive sequences constrained in this conformation, confer specific reactivity to different sites on the collagens. We plan to elucidate this important basis of collagen function by examining the conformation of isolated sequences from structural and reactive regions of collagen, experimentally through the use of synthetic polypeptide models, and using theoretical techniques of energy and molecular mechanics and dynamics calculations and simulation of conformation. The intramolecular interactions involved in the stability of structural and reactive conformations will be determined using both experimental and theoretical procedures.