Simulation of the folding / unfolding thermodynamics of protein A

Angel Garcia
Los Alamos National Laboratory

We study the folding mechanism of a three-helix bundle protein at atomic resolution, including effects of explicit water. Multiple transitions between the unfolded ensemble and the native minimum are actually observed. Using replica exchange molecular dynamics we perform sufficient sampling over a wide range of temperatures to obtain the free energy, entropy and enthalpy surfaces as a function of tructural reaction coordinates. Simulations were started from different configurations covering the folded and un-folded states. Since many transitions between all minima at the free energy surface are observed, a quantitative on of
the free energy barriers and the ensemble of configurations associated with them are now possible. The kinetic bottlenecks for
folding can be determined from the thermal ensembles of structures at the free energy barriers, provided the kinetically de-
termined transition state ensembles (TSE) are similar to the ones determined from free energy barriers. A mechanism incorporating the interplay among backbone ordering, side-chain packing, and de-solvation arises from these calculations. Large phi values arise
not only from native contacts that mostly form at the transition state, but also from contacts already present in the unfolded state that are partially destroyed at the transition. This work
was done in collaboration with Jose N. Onuchic (UCSD).

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