Under the sea: The effect of high pressure on marine biochemistry

海洋中的生命以高静水压力的形式呈现出独特的环境压力，在其最深处可以达到1000个大气压。高压对构成活组织的大分子有严重的影响。例如，增加压力通常会导致蛋白质亚基的解离、局部构象变化或在最极端的情况下，完全或部分蛋白质解折叠。所有这些变化都会导致蛋白质功能丧失，与生命不相容。尽管如此，估计有超过1500种海洋生物生活在超过100个大气压的压力下。这是由于进化适应，使他们能够科普高压的压力。其中一种适应是深海鱼类蛋白质的氨基酸序列与浅水鱼类亲属相比发生了替换。然而，这些取代使蛋白质抵抗压力失活的机制目前尚不清楚。此外，海洋污染日益令人关切，完全不知道这些抗压适应是否影响深海生物代谢化学污染物的能力。该研究方案的长期目标是利用计算技术阐明深海生物科普高静水压力影响的物理化学机制，并研究这些适应是否影响参与重要代谢途径的蛋白质的功能。我和我的学生将使用最先进的分子动力学和量子化学方法来实现这些目标，以比较两种不同蛋白质的深海和浅水同系物的体积，热力学和催化性质：乳酸脱氢酶，一种充分表征的抗压蛋白，和芳烃受体，一种与污染物分解有关的蛋白质，最近被发现具有高压适应性。这项研究将大大增加我们对序列、结构和压力之间相互作用的理解，其结果将在抗压蛋白质的合理设计中具有应用价值

Life in the ocean presents a unique environmental stress in the form of high hydrostatic pressure, which can reach up to 1000 atmospheres at its greatest depth. High pressure has serious effects on the macromolecules which make up living tissue. For example, increasing pressure will typically result in the dissociation of protein subunits, local conformational changes or in the most extreme cases, complete or partial protein unfolding. All of these changes will result in loss of protein function and are incompatible with life. Despite this, over 1500 species of marine organisms are estimated to live at pressures greater than 100 atmospheres. This is due to evolutionary adaptations that allow them to cope with the stresses of high pressure. One such adaptation is substitutions in the amino acid sequence of the proteins of deep-sea fish compared with their shallow-water relatives. However, the mechanism by which these substitutions allow the proteins to resist pressure inactivation is currently unknown. In addition, ocean pollution is an increasing concern and it is completely unknown whether these pressure-resistant adaptations affect the ability of deep-sea organisms to metabolize chemical pollutants. The long-term goals of this research program are to use computational techniques to shed light on the physico-chemical mechanisms used by deep-sea organisms to cope with the effects of high hydrostatic pressure, and to study whether these adaptations affect the functionality of proteins involved in important metabolic pathways. My students and I will work towards these goals using state of the art molecular dynamics and quantum chemistry methods to compare the volumetric, thermodynamic and catalytic properties of deep-sea and shallow-water homologs of two different proteins: lactate dehydrogenase, a well-characterised pressure-resistant protein, and the aryl hydrocarbon receptor, a protein involved in the breakdown of pollutants which has just recently been discovered to have high pressure adaptations. This research will greatly increase our understanding of the interplay between sequence, structure and pressure, and the outcomes will have applications in the rational design of pressure-resistant proteins