Impact of naturally occurring osmolytes on protein structure and energetics

天然存在的渗透剂对蛋白质结构和能量学的影响

• 批准号: 7982984
• 负责人: Jorg Rosgen
• 金额: $ 22.91万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982984
• 关键词: Affect; Behavior; Biochemistry; Biological; Biophysics; Brain; Brain Edema; Cell Volumes; Cell physiology; Cells; Chemicals; Clinical; Companions; Complex; Couples; Crystallization; Cytoplasm; Diabetes Mellitus; Disease; Drug Formulations; Drug Industry; Foundations; Free Energy; Goals; Hand' s disease; Health; Hydration status; Investigation; Kidney; Knowledge; Lead; Measurement; Measures; Mediating; Methods; Microscopic; Molecular; Molecular Chaperones; Nature; Organ; Organism; Outcome; Pathology; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Play; Polycystic Kidney Diseases; Positioning Attribute; Process; Property; Proteins; Regulation; Relative (related person); Research; Research Personnel; Role; Side; Sodium Chloride; Solutions; Solvents; Stress; Structure; System; Thermodynamics; Tissues; Urea; Vaccines; Vertebral column; Water; Work; antidiuresis; base; biological adaptation to stress; brain cell; coping; glucosyltransferase E; kidney cell; kidney medulla; macromolecule; practical application; preference; present value; pressure; prevent; protein folding; protein function; protein protein interaction; protein structure; response

DESCRIPTION (provided by applicant): Protecting osmolytes are responsible for the kidney medulla's extraordinary ability to cope with intracellular urea concentration as high as 1.5M. These small organic molecules are common in cells of many tissues, and an important part of their action in kidney is to stabilize intracellular proteins against the deleterious effects of urea. Besides being essential for our survival, imbalances in osmolyte levels play key roles in such conditions as polycystic kidney disease, diabetes mellitus, and brain edema. Though many biological roles of osmolytes arise from their solvation of proteins, it is unknown how protein solvation facilitates these roles. This gap in knowledge prevents a complete understanding of osmolyte effects and their roles in normal and disease states. Our long-term goal is to understand how interactions among osmolytes, water, and biomolecules give rise to osmotic stress response on the one hand, and disease on the other. Using measurements of the transfer free energy of protein side-chain and peptide backbone groups (GTFEs) from water to osmolyte solution, we recently made the remarkable discovery of how to predict the energetics of protein-stability in osmolytes. Our aims are to consolidate and use this ability to determine the underlying forces responsible for protein stability, and to the predict energetic effects of osmolytes on contraction and accretion of structure in denatured ensembles. We will extend our use of GTFEs to enable predictions of protein-protein interaction free energies, to better understand how fluctuating osmolyte concentrations affect key protein-protein interactions vital to cellular responses, and determine the extent to which kidney osmolytes act synergistically, negatively, or independently in affecting the properties of proteins. We aim to merge our ability to predict the energetics of protein stability and solvation effects with Kirkwood-Buff approaches that structurally relate water*osmolyte*protein interaction with the energetics, to give a considerably more detailed mechanistic understanding of protein solvation than currently exists. Relevance: This project will lead to a better understanding of how osmolytes protect proteins from unfolding under harsh condition, and how imbalances in osmolyte levels can contribute to the pathology of such conditions as polycystic kidney disease, diabetes mellitus, and brain swelling. Our work will have practical applications in the pharmaceutical industry for stabilization of vaccines and protein/ peptide drugs.

描述（由申请方提供）：保护性渗透调节剂是肾髓质科普高达1.5 M的细胞内尿素浓度的非凡能力的原因。这些小的有机分子在许多组织的细胞中是常见的，并且它们在肾脏中的作用的重要部分是稳定细胞内蛋白质以对抗尿素的有害作用。除了对我们的生存至关重要外，渗透压水平的不平衡在多囊肾病、糖尿病和脑水肿等疾病中起着关键作用。虽然渗透剂的许多生物学作用来自于它们对蛋白质的溶剂化，但蛋白质溶剂化如何促进这些作用尚不清楚。这种知识上的差距阻碍了对渗透剂效应及其在正常和疾病状态下的作用的全面理解。我们的长期目标是了解渗透压物质、水和生物分子之间的相互作用如何一方面引起渗透压反应，另一方面引起疾病。利用蛋白质侧链和肽骨架基团（GTFEs）从水到渗透剂溶液的转移自由能的测量，我们最近做出了如何预测渗透剂中蛋白质稳定性的能量学的显着发现。我们的目标是巩固和使用这种能力，以确定负责蛋白质稳定性的基本力量，并预测能量的渗透剂收缩和增生的结构在变性合奏的影响。我们将扩展我们的使用GTFE，使蛋白质-蛋白质相互作用的自由能的预测，以更好地了解波动的渗透压浓度如何影响关键的蛋白质-蛋白质相互作用至关重要的细胞反应，并确定在何种程度上肾脏渗透压协同作用，负面的，或独立影响蛋白质的性质。我们的目标是合并我们的能力，预测能量的蛋白质的稳定性和溶剂化的影响与柯克伍德-布夫的方法，结构相关的水 * 渗透剂 * 蛋白质相互作用的能量，给一个相当详细的机械蛋白质溶剂化的理解比目前存在的。相关性：该项目将导致更好地了解渗透剂如何保护蛋白质在恶劣条件下展开，以及渗透剂水平的不平衡如何有助于多囊肾病，糖尿病和脑肿胀等疾病的病理学。我们的工作将在制药工业中用于稳定疫苗和蛋白质/肽药物。