Urea is a commonly used chemical denaturant in protein folding studies, whose molecular mechanism has attracted much debate. We report the first computation of the changes in the preferential interaction of the protein upon urea denaturation, obtained from extensive Replica Exchange MD simulations of Trp-cage in presence of urea. Our study shows that the interaction of the protein sidechains with urea makes the largest contribution to the change in stability of the protein upon addition of urea, rather than the protein backbone as is widely believed. TMAO is a protecting osmolyte that offsets the effect of urea on protein stability, in a 2:1 ratio of urea and TMAO. Since current forcefields were unable to capture the phenomena, we have developed new parameters for TMAO that incorporates realistic water-TMAO interactions using osmotic pressure data. The new model captures the preferential exclusion of TMAO from the protein surfaces.

Simulations of the effects of urea and TMAO on protein stability

243rd National Meeting (2012)

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