  The mechanisms of cold- and pressure-denaturation of proteins are matter of
debate and are commonly understood as due to water-mediated interactions. Here
we study several cases of proteins, with or without a unique native state, with
or without hydrophilic residues, by means of a coarse-grain protein model in
explicit solvent. We show, using Monte Carlo simulations, that taking into
account how water at the protein interface changes its hydrogen bond properties
and its density fluctuations is enough to predict protein stability regions
with elliptic shapes in the temperature-pressure plane, consistent with
previous theories. Our results clearly identify the different mechanisms with
which water participates to denaturation and open the perspective to develop
advanced computational design tools for protein engineering.
