The origin of pressure resistance in deep-sea lactate dehydrogenase

High hydrostatic pressure has a dramatic effect on biochemical systems, as exposure to high pressure can result in structural perturbations ranging from dissociation of protein complexes to complete denaturation. The deep ocean presents an interesting paradox since it is teeming with life despite the high-pressure environment. This is due to evolutionary adaptations in deep-sea organisms, such as amino acid substitutions in their proteins, which aid in resisting the denaturing effects of pressure. However, the physico-chemical mechanism by which these substitutions can induce pressure resistance remains unknown. Here, we use molecular dynamics simulations to study pressure-adapted lactate dehydrogenase from the deep-sea abyssal grenadier (C. armatus), in comparison with that of the shallow-water Atlantic cod (G. morhua). Alchemical thermodynamic integration and the Archimedean Displacement Method were used to determine whether pressure resistance is due to a thermodynamic stabilization of the native state of the protein or to an increase in the volume of the denatured state. We report that the amino acid substitutions destabilize the folded protein, but pressure resistance is achieved through an increase in compressibility for the pressure-adapted protein.