Conformational Change in Molecular Biology

分子生物学中的构象变化

• 批准号: 7432595
• 负责人: Martin Karplus
• 金额: $ 30.85万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-12-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7432595
• 关键词: ATP Hydrolysis; ATP Synthesis Pathway; ATP phosphohydrolase; Active Sites; Algorithms; Antifungal Agents; Bacillus (bacterium); Base Pairing; Binding; Biological Factors; Biology; Catalysis; Catalytic Domain; Cell physiology; Cells; Chemistry; Class; Collaborations; Complement; Complex; Coupling; DNA; DNA Polymerase I; DNA Structure; DNA biosynthesis; DNA chemical synthesis; DNA-Protein Interaction; Data; Development; Diphosphates; Disease; Energy-Generating Resources; Enzymes; Equilibrium; Free Energy; Future; Generations; Genetic; Goals; Grant; Hydrolysis; Knowledge; Laws; Lead; Life; Malignant Neoplasms; Measurement; Mechanics; Methods; Mitochondria; Modeling; Molecular; Molecular Biology; Molecular Conformation; Molecular Machines; Molecular Motors; Motor; Mutate; Names; Nature; Organism; Pathway interactions; Phosphotransferases; Physics; Play; Polymerase; Procedures; Process; Proteins; Proton-Motive Force; Range; Reaction; Replication Error; Research; Resolution; Role; Rotation; Sampling; Series; Short-Term Memory; Signaling Protein; Simulate; Solvents; Staging; Structure; System; Thermodynamics; Torque; Work; base; cancer therapy; chemical kinetics; design; improved; inhibitor/antagonist; interest; molecular dynamics; polymerization; professor; quantum; research study; scaffold; simulation

DESCRIPTION (provided by applicant): The long term goal of molecular approaches to biology is to describe living systems in terms of the laws of chemistry and physics. Theoretical methods can serve to complement experimental studies to obtain an understanding of the molecular machines that play a vital role in the function of living cells. The two molecular motors Fi-ATPase and DNA polymerase I (pol I) will be investigated. The rotatory nanomotor, FoFi-ATP synthase, of which Fi-ATPase is the globular catalytic moiety, is responsible for the synthesis of ATP, the energy currency of cells. The model for this motor developed in the previous grant period raises specific questions, which will be investigated. How is the rotation of the y-subunit induced by the conformational changes of the catalytic p-subunits during the ATP hydrolysis cycle? What conformations of the catalytic p-subunits are involved in catalysis? For DNA pol I, the translocation step in DNA replication, which follows incorporation of a new base into the primer strand, will be elucidated. The pathway from the pre-translocation to the post-translocation state will be determined and utilized to obtain the atomic details of the key steps involved. The nature of "short-term memory" (i.e., the effect of mismatches in the synthesized DNA, away from the active site, on translocation) will be studied. For both motors, classical dynamical methods (in particular, the new restricted perturbation targeted molecular dynamics algorithm) will be used to determine the nature of the pathways and quantum mechanical/molecular simulations will be employed to study the reactions involved. The results will increase our understanding of the diseases caused by malfunction of these motors. Macro-cyclic inhibitors of mitochondrial FoFi-ATPase will be developed as a possible approach to cancer therapy. A knowledge of the mechanism of two molecular motors, FoFi-ATPase, which makes ATP, and DNA polymerase I, which accurately copies DNA, is essential for a description of cellular function. We will study how these motors work and employ the results to find inhibitors for ATP synthesis in the mitochondria, a suggested treatment of cancer, and to interpret the effect of replication errors in DNA synthesis by polymerases.

描述（由申请人提供）：生物学分子方法的长期目标是描述化学和物理定律的生命系统。理论方法可以用来补充实验研究，以了解对活细胞功能起着至关重要作用的分子机器的理解。将研究两个分子电机FI-ATPase和DNA聚合酶I（POL I）。旋转纳米运动型FOFI-ATP合酶，其中FI-ATPase是球形催化部分，是造成细胞能量货币ATP的合成。该电动机的模型在上一个赠款期间开发的，提出了特定的问题，这将进行研究。在ATP水解循环中，催化P-亚基的构象变化诱导Y-亚基的旋转如何？催化中涉及催化P-亚基的哪些构象？对于DNA pol I，将阐明DNA复制中的易位步骤，该步骤将在引物链中掺入新的碱后。将确定并利用从递交前到转换后状态的途径，以获取所涉及的关键步骤的原子细节。将研究“短期记忆”的性质（即，将研究合成DNA中不匹配的效果，远离活性位点，对易位的影响）。对于这两个电动机，将使用经典动力学方法（特别是，新的受限制扰动靶向分子动力学算法）来确定途径的性质，并将使用量子力学/分子模拟来研究所涉及的反应。结果将增加我们对这些电机故障引起的疾病的理解。线粒体FOFI-ATPase的宏环抑制剂将被开发为癌症治疗的一种方法。对两个分子电机Fofi-ATPase的机制的了解，该机制使ATP和DNA聚合酶I（准确复制DNA）对于描述细胞功能至关重要。我们将研究这些电动机如何工作并采用结果来找到线粒体中ATP合成的抑制剂，建议对癌症进行治疗，并解释通过聚合酶在DNA合成中复制误差的影响。