Molecular simulations suggest protein salt bridges are uniquely suited to life at high temperatures.

A series of explicit solvent molecular dynamics simulations has been performed to investigate the temperature dependence of salt bridge interactions between two freely diffusing amino acids. The simulations, performed at 25, 50, 75, and 100 degrees C, allow a large number of distinct association and dissociation events to be directly observed, without the imposition of additional forces to drive association. Analysis of contact frequencies for atom pairs demonstrates that the number of salt bridge contacts between the two molecules is unaffected by temperature, whereas the numbers of hydrophobic and polar contacts are greatly diminished. A second, independent set of simulations-using rigid, prototypical molecule types-allows the differing temperature dependences of hydrophobic, polar, and salt bridge interactions to be unambiguously examined. In the prototype molecule simulations, the salt bridge interaction is found to substantially increase in stability at 100 degrees C relative to 25 degrees C. This difference in behavior between flexible amino acids and rigid prototype molecules is perhaps a direct manifestation of the effects of conformational entropy on association thermodynamics. Overall, the results demonstrate that salt bridge interactions are extremely resilient to temperature increases and, as such, are uniquely suited to promoting protein stability at high temperatures.