Physical Principles of Biomolecular Recognition, Self-Assembly and Regulation

生物分子识别、自组装和调控的物理原理

• 批准号: 6107989
• 负责人: Sergey Leikin
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6107989
• 关键词: DNA; biophysics; chemical aggregate; collagen; cytoskeleton; intermolecular interaction; macromolecule; protein denaturation; structural biology; thermostability

teractions between various biological helices control protein folding and assembly, DNA packing, protein-DNA interactions, connective tissue formation and stability, and many other processes responsible for normal function and pathology in living organisms. By combining direct measurements with rigorous physical theories we continued to advance our understanding of these most basic molecular recognition reactions. Our most significant achievements during the past year were: (1) Development of a theory of electrostatic interactions driving poly- and mesomorphous transitions in dense aggregates of long, natural DNA. Based on this theory, we proposed mechanisms for the B to A transition in DNA fibers upon decreasing humidity, for the stabilization of the B form by Li+ ions, and for the transitions from hexagonal to monoclinic or orthorhombic packing of DNA in the aggregates. These phenomena were observed already in early, pioneering studies by Franklin et al. and by Wilkins et al., but they were never fully understood. (2) Measurement of the effects of protein denaturants on interactions between collagen helices in fibers. Our results suggested a novel mechanism of temperature-induced collagen fibrillogenesis. Apparently, elevated temperature causes local melting and structural rearrangements of collagen triple helices in a vicinity of recognition sites. This promotes correct inter-molecular recognition and fiber assembly. Urea, acetamide, and some of their methylated derivatives facilitate the process by easing the local melting. As a result, they enhance the temperature dependence of forces between collagen helices. However, these protein denaturants also bind non-specifically to collagen backbone intensifying hydration repulsion between triple helices. The latter effect, which is likely to be common for most proteins, overpowers the recognition enhancement leading to overall suppression of fibrillogenesis."

各种生物螺旋之间的相互作用 控制蛋白质折叠和组装、DNA 包装、蛋白质-DNA 相互作用、结缔组织的形成和稳定性等 负责正常功能和病理的其他过程 活的有机体。通过将直接测量与严格的 我们继续加深对物理理论的理解 这些最基本的分子识别反应。我们最 过去一年取得的重大成就有：（1） 发展静电相互作用驱动多聚的理论 以及长的致密聚集体中的介晶转变， 天然DNA。基于这个理论，我们提出了机制 DNA 纤维中 B 到 A 的转变 湿度，用于通过 Li+ 离子稳定 B 形式，并用于 从六方晶系转变为单斜晶系或斜方晶系 DNA 在聚集体中的堆积。这些现象是 富兰克林等人在早期的开创性研究中已经观察到了这一点。和 威尔金斯等人提出了这一观点，但他们从未被完全理解。 (2) 测量蛋白质变性剂对相互作用的影响 纤维中的胶原蛋白螺旋之间。我们的结果暗示了一部小说 温度诱导胶原纤维生成的机制。 显然，升高的温度会导致局部熔化和 胶原蛋白三螺旋附近的结构重排 识别位点。这促进了正确的分子间识别 和纤维组装。尿素、乙酰胺及其一些 甲基化衍生物通过缓解局部反应来促进该过程 融化。因此，它们增强了温度依赖性 胶原蛋白螺旋之间的力。然而，这些蛋白质 变性剂也非特异性地结合到胶原蛋白骨架上 增强三螺旋之间的水合作用排斥力。后者 效应，这对于大多数蛋白质来说可能是常见的， 压倒识别增强导致整体 抑制原纤维形成。”