Abstract
Urea is a denaturant commonly used in protein folding studies. Simulation studies of the effect of urea on protein stability have concentrated on how urea unfolds proteins - not on how urea affects the folding/unfolding equilibrium. Here we report the first simulation studies of the reversible folding and unfolding equilibrium of a protein - the Trp-Cage miniprotein. Replica exchange MD was performed in all atomic detail, starting from an unfolded (extended) configuration in three different solvent conditions viz. 2M, 4M and 6M in Urea. The Kirkwood-Buff model for Urea was employed. Fifty replicas of the system at each concentration were simulated for 150 ns per replica per urea concentration (22.5 microseconds total simulation time), enabling us to obtain folding-unfolding equilibrium data in the temperature range of 283 K to 579 K. In addition, we have performed REMD simulations in 0 M urea i.e pure water (4 microseconds total simulation time). During these simulations we observe all replicas to fold and unfold multiple times. The equilibrium properties, as a function of T and [Urea], show a clear shift in equilibrium towards the unfolded state with increasing urea concentration. Details of the solvent structure around the protein backbone and side chains will be presented.This work was supported by the NSF MCB-0543769.
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