Kinetics of breaking a salt-bridge critical in protein unfolding

The rate of breaking an Arg–Glu salt bridge on the surface of a globular protein (Staphylococcal nuclease) is determined by using molecular dynamics simulations to derive the free energy activation barrier to dissociation and the pre-exponential rate factor for that reaction. The dissociation barrier obtained is 7 kcal/mol. The pre-exponential factor is derived using a novel method in which simulations are performed for the same system with the salt bridge weakened such that the rate can be observed directly. Combining the prefactor thus obtained (5×1011 s−1) with the above dissociation barrier height yields an estimated lifetime of the salt-bridge of 200 ns, suggesting that surface salt-bridges can cause significant kinetic barriers to protein folding or unfolding.