Kinetics of macromolecular complex assembly and regulation

大分子复合物组装和调控的动力学

• 批准号: 9121787
• 负责人: William Monroe Jacobs
• 金额: $ 5.43万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-10 至 2018-05-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121787
• 关键词: Affect; Binding; Biological Models; Biological Process; Biomimetics; Case Study; Cells; Complex; DNA; Databases; Disease; Engineering; Equilibrium; Escherichia coli; Free Energy; Goals; Investigation; Kinetics; Knowledge; Lead; Macromolecular Complexes; Methods; Modeling; Molecular; Molecular Chaperones; Mutation; Nanostructures; Nanotechnology; Nucleic Acids; Nucleoproteins; Nucleosomes; Outcome; Pathway interactions; Process; Production; Property; Proteins; Proteome; Proteomics; Regulation; Ribosomes; Role; Spliceosomes; Structure; Testing; Variant; Work; base; computerized tools; coping; design; improved; in vivo; multicatalytic endopeptidase complex; novel; novel therapeutic intervention; physical model; public health relevance; reconstitution; research study; self assembly; simulation; stoichiometry; structural biology; theories; therapeutic development

 DESCRIPTION (provided by applicant): Although the misassembly of protein and nucleoprotein complexes is implicated in many regulatory disorders, we have extremely limited knowledge of the mechanisms by which these complexes assemble in vivo. Because many proteins must associate into higher-order assemblies in order to carry out their biological functions, predicting the self-assembly of these complexes is crucial for understanding the organization and regulation of the proteome. Experimental investigations of the assembly of these complexes are complicated by the fact that many essential complexes, including the ribosome and the proteasome, contain dozens of subunits that assemble in a highly cooperative manner. Furthermore, it is now known that assembly in vivo differs significantly from reconstitution experiments conducted under dilute conditions, particularly due to the presence of molecular chaperones that act as assembly co-factors. New theoretical approaches are thus needed to cope with this complexity and to identify the physical principles governing robust self-assembly and regulation at the proteomic level. Building on a powerful theory of self-assembly that I have recently developed to describe DNA-based nanostructures, I shall establish a novel theoretical approach for predicting the assembly pathways of protein and nucleoprotein complexes. This approach will provide a considerably more complete picture of the mechanism of assembly than can be obtained from experiments alone and is orders of magnitude more efficient than conventional simulations. Leveraging this efficiency to perform computational screens that were previously intractible, I shall test the hypothesis that nucleoprotein complexes have evolved to optimize the rate of assembly. I shall also investigate the sensitivity of self-assembly to variations in subunit stoichiometries, and I shall apply the theory to examine the role of chaperones in promoting accurate assembly. These theoretical predictions will be tested with two case studies of specific model systems. This work will lead to an improved understanding of regulation at the proteomic level. A physically rigorous theory will establish general principles of the self-assembly of macromolecular complexes. Understanding the mechanisms of chaperone-assisted self-assembly will also enable the rational engineering of biomimetic chaperones, which hold great potential for altering the production of complexes in vivo, thus guiding the development of therapeutic strategies for a wide range of protein-misassembly disorders.