(665a) Destabilization of Proteins in Extreme Conditions: Molecular Simulations of the Denaturation of Trp-Cage Miniprotein
Proteins are stable in their compact, folded structures only in a narrow range of physiological conditions. Deviation from these conditions, such as changes in temperature and salt concentrations, can destabilize the folded structures. Investigating the mechanism(s) of protein denaturation induced by these extreme conditions has a fundamental importance in understanding of the evolution of organisms with extreme habitats and formulating effective long-term preservation strategies for biological therapeutics. Using replica-exchange molecular dynamics simulations, we examine the mechanisms of cold- and salt-induced denaturation of a fully-atomistic model of the Trp-cage miniprotein, and we make direct comparison with the unfolding behavior at high temperatures. In contrast to the complete unraveling of the secondary and tertiary structures observed during heat denaturation, the cold-denatured structure of the Trp-cage is compact and partially folded with stable alpha-helix, despite the loss of salt bridges. We also find that the salt-denatured structures exhibit a strong resemblance to the cold-unfolded Trp-cages. The mechanism of cold- and salt-induced protein denaturation is examined by analyzing the structural change, thermodynamic quantities, and protein-solvent interaction.