"Probing the Hydrogen Bonding Properties of the Protein-Water Interface and its Effects on Protein Stability, Function and Dynamics"

“探索蛋白质-水界面的氢键特性及其对蛋白质稳定性、功能和动力学的影响”

• 批准号: 371373-2012
• 负责人: Khajehpour, Mazdak
• 金额: $ 2.04万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=595849
• 关键词: Probing; Hydrogen; Bonding; Properties; Protein

The common component of all proteins is their aqueous solvent shell. Arguably, the most important role in protein structure and dynamics is played by the water solvent molecules. However (even after more than four decades of research), it is the role of water that remains the least understood of all. When a protein is dissolved in aqueous solvent it divides the solvent molecules into two groups: bulk water molecules and the molecules that constitute the protein hydration shell. Early experiments in protein hydration demonstrate that minimal hydration is required for protein structure and function pointing to the crucial role of the protein hydration sphere. The current research focus of my group is on understanding the role that solvent water molecules -especially those molecules located in the protein hydration sphere, play in ensuring proteins assume the correct fold and function. An extremely powerful method to better understand the role of the hydration sphere is to perturb the properties of these waters with chemical agents called osmolytes and subsequently determine the effect of this perturbation on the protein structure and function. Osmolytes are molecules produced by living organisms that stabilize proteins under highly denaturing conditions. Molecules such as TMAO (Trimethylamine N-oxide) stabilize the proteins by counteracting the effects of high concentrations of urea in the cells of marine organisms, while species such as betaine, sorbitol and inositol play a similar role in kidney cells. Although it has been known for a long time that osmolytes are strong stabilizers of the protein folded state, their mechanism of action on proteins is still not fully understood at the molecular level. However, most interpretations agree that the origin of osmolyte induced stabilization lies in the changes that these molecules effect on the hydration sphere. Understanding the mechanism by which osmolytes work will provide us with a framework for investigating the role of hydration water in crowded cellular environments, a long-term goal in our quest in understanding the role water plays in the biochemistry of real cells.

所有蛋白质的共同组成部分是它们的水性溶剂壳。可以说，水溶剂分子在蛋白质结构和动力学中发挥着最重要的作用。然而（即使经过四十多年的研究），水的作用仍然是人们最不了解的。当蛋白质溶解在水性溶剂中时，它将溶剂分子分成两组：大量水分子和构成蛋白质水合壳的分子。蛋白质水合的早期实验表明，蛋白质结构和功能需要最小的水合作用，这表明蛋白质水合球的关键作用。我的团队目前的研究重点是了解溶剂水分子的作用-特别是那些位于蛋白质水合球的分子，在确保蛋白质呈现正确的折叠和功能方面发挥作用。为了更好地理解水合球的作用，一种非常有效的方法是用称为渗透剂的化学试剂扰动这些沃茨的性质，然后确定这种扰动对蛋白质结构和功能的影响。渗透调节剂是由活生物体产生的分子，其在高度变性条件下稳定蛋白质。分子如TMAO（三甲基胺N-氧化物）通过抵消海洋生物细胞中高浓度尿素的影响来稳定蛋白质，而甜菜碱、山梨糖醇和肌醇等物质在肾细胞中发挥类似作用。虽然渗透调节剂是蛋白质折叠状态的强稳定剂已经知道很长时间了，但它们对蛋白质的作用机制在分子水平上仍然没有完全理解。然而，大多数解释都认为渗透剂诱导稳定的起源在于这些分子对水化球的影响。了解渗透调节剂的工作机制将为我们提供一个框架，用于研究水合水在拥挤的细胞环境中的作用，这是我们寻求了解水在真实的细胞生物化学中所起作用的长期目标。