MOLECULAR BASIS OF COLLAGEN REACTIVITY

胶原蛋白反应性的分子基础

• 批准号: 3157996
• 负责人: RAJENDRA S BHATNAGAR
• 金额: $ 15.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-04-01 至 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3157996
• 关键词: Raman spectrometry; circular dichroism; collagen; computer graphics /printing; conformation; high performance liquid chromatography; iminoacid; infrared spectrometry; molecular pathology; molecular site; nuclear magnetic resonance spectroscopy; peptide chemical synthesis; physical model; protein denaturation; protein sequence; protein structure

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.

胶原蛋白参与了许多相互作用，这些相互作用有助于 形式、功能、生理学和病理学以及所有结缔组织。 胶原蛋白相互作用的干扰有助于病理生物学 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， 会出现发育障碍。 为了了解生理学 和病理生物学的胶原蛋白，有必要阐明分子 胶原反应的基础。 我们提出这项建议的目的是 阐明反应位点的性质和物理化学因素 控制它们的反应性 胶原蛋白的反应位点是 轴向分布在三股螺旋上。 我们的假设是 这些位点的生物特异性取决于不同的和特定的 分子观点提供了相互作用的物种。 均匀的 沿着三螺旋的整个长度沿着延伸的构象将 排除这种特殊性。 为了让活性位点表达 具体的分子观点在配体的方法，这些区域 三股螺旋的构象必须至少短暂地偏离 存在于分子的其余部分。 这一点得到以下观察结果的支持： 胶原蛋白的某些相互作用是通过 条件 根据我们的假设， 反应性不仅取决于特定的序列标记， 稳定三螺旋的链间相互作用的差异 在反应位点和邻近的非反应区域中， 促进了一个独特的分子视角的介绍， 接近配体。 我们进一步提出， 序列支持三螺旋构象的程度， 常用的实验技术显示，相对而言， 限制在这种构象中的亚氨基稀疏反应序列，赋予 对胶原蛋白上不同位点的特异性反应。 我们计划 通过检查胶原蛋白的结构，阐明胶原蛋白功能的重要基础。 结构和反应区域的分离序列的构象 胶原蛋白，实验上通过使用合成多肽模型， 运用能量和分子力学的理论技术， 动力学计算和构象模拟。 分子内 结构和反应稳定性中的相互作用 将使用实验和理论方法确定构象 程序.