Grant: Discovery Grants Program - Individual

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