Protein Interfaces and Aggregation

蛋白质界面和聚集

• 批准号: 10405469
• 负责人: Bernard MONTGOMERY PETTITT
• 金额: $ 31.93万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405469
• 关键词: Alpha Granule; Amino Acid Sequence; Automobile Driving; Biological Models; Cell physiology; Cells; Cellular Structures; Characteristics; Chemicals; Computing Methodologies; Coupling; Dependence; Diagnostic; Diffuse; Diffusion; Disease; Entropy; Environment; Equilibrium; Exhibits; Financial compensation; Free Energy; Future; Grain; Kinetics; Liquid substance; Measures; Modeling; Molecular; Molecular Conformation; Nature; Nucleic Acids; Nucleotides; Organelles; Pathologic; Peptides; Periodicity; Phase; Phase Transition; Phosphorylation; Physical condensation; Physiological; Play; Process; Property; Proteins; Role; Serine; Signal Transduction; Solid; Solubility; Solvents; Structure; Surface; System; Testing; Therapeutic; Thermodynamics; balance testing; computerized tools; driving force; enthalpy; experimental study; field theory; flexibility; inorganic phosphate; insight; intermolecular interaction; macromolecule; membrane model; polypeptide; preference; protein protein interaction; protein structure; public health relevance; simulation; stress granule; theories

ABSTRACT Nonenveloped organelles govern many cellular functions including aspects of signaling. These cellular bodies are made up of proteins and nucleic acids which have condensed, or phase separated out of the components within the cell. The coupling of structure and miscibility properties of polypeptides and nucleotides underly the formation of non-enveloped organelles or biomolecular condensates. We propose theoretical and computational methods to quantify the contributions of number of protein components, structural/conformational disorder and phosphorylation to biomolecular condensate formation. Each of the polypeptide components interact and form an interface with other molecules in the biomolecular condensate. These interactions drive the formation of these cellular structures. This is not a protein or peptide interface prediction project, but rather we seek to understand the interactions and entropic components of the underlying free energy surface driving the creation of the solubility limit and the consequent phase transition forming the condensates. We propose to calculate the properties of polypeptide biomolecular condensates by simulating and analyzing the liquid-liquid phase separation at the all-atom model level. We will explicitly consider the role of peptide disorder, the number of components and their chemical characteristics that allow condensation out of the cytosolic mixture. Deciphering the thermodynamic manifold, entropic versus enthalpic driving forces as well as compositional dependences is necessary to understand the formation and stability of these cellular physiological assemblies. Once condensed the kinetics of the system is governed in part by the diffusion of the components both within the condensate and in its formation or dissolution. The rate constants for polypeptide transport will be explicitly calculated to consider the effects of sequestration given the properties of the sequence. Differentiation of physiological versus pathological assemblies and, as such, plausible therapeutic solutions targeting these structures will not be possible without these fundamental mechanistic insights.

抽象的 非发达细胞器控制着许多细胞功能，包括信号的各个方面。这些细胞体 由凝结的蛋白质和核酸组成，或从组成部分分离的相位 在细胞内。结构和多肽和核苷酸的结构偶联 形成非发育的细胞器或生物分子冷凝物。我们提出了理论和计算 量化蛋白质成分数量，结构/构象障碍和的方法 磷酸化对生物分子冷凝物的形成。每个多肽成分相互作用并形成 与生物分子冷凝物中其他分子的界面。这些互动推动了这些相互作用 细胞结构。这不是蛋白质或肽接口预测项目，而是我们试图理解 基础自由能表面的相互作用和熵成分驱动创造的 溶解度极限和随之而来的相变形成冷凝物。我们建议计算 通过模拟和分析液态液相的多肽生物分子冷凝物的特性 在全原子模型级别的分离。我们将明确考虑肽障碍的作用，数量 成分及其化学特性允许从胞质混合物中凝结。解密 热力学歧管，熵与焓驱动力以及组成依赖性是 了解这些细胞生理组件的形成和稳定性所必需。一旦凝结 系统的动力学部分由凝结物中的组件的扩散和 在其形成或溶解中。多肽运输的速率常数将被明确计算为考虑 给定序列的特性，隔离的影响。生理与 病理组装及其针对这些结构的合理治疗解决方案将不是 没有这些基本的机械见解。