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Origins of protein denatured state compactness and hydrophobic clustering in aqueous urea: Inferences from nonpolar potentials of mean force
Author(s) -
Shimizu Seishi,
Chan Hue Sun
Publication year - 2002
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.10263
Subject(s) - urea , aqueous solution , chemistry , hydrophobic effect , potential of mean force , random coil , denaturation (fissile materials) , solvent , chaotropic agent , thermodynamics , heat capacity , chemical physics , molecular dynamics , crystallography , organic chemistry , computational chemistry , circular dichroism , physics , nuclear chemistry
Free energies of pairwise hydrophobic association are simulated in aqueous solutions of urea at concentrations ranging from 0–8 M. Consistent with the expectation that hydrophobic interactions are weakened by urea, the association of relatively large nonpolar solutes is destabilized by urea. However, the association of two small methane‐sized nonpolar solutes in water has the opposite tendency of being slightly strengthened by the addition of urea. Such size effects and the dependence of urea‐induced stability changes on the configuration of nonpolar solutes are not predicted by solvent accessible surface area approaches based on energetic parameters derived from bulk‐phase solubilities of model compounds. Thus, to understand hydrophobic interactions in proteins, it is not sufficient to rely solely on transfer experiment data that effectively characterize a single nonpolar solute in an aqueous environment but not the solvent‐mediated interactions among two or more nonpolar solutes. We find that the m ‐values for the rate of change of two‐methane association free energy with respect to urea concentration is a dramatically nonmonotonic function of the spatial separation between the two methanes, with a distance‐dependent profile similar to the corresponding two‐methane heat capacity of association in pure water. Our results rationalize the persistence of residual hydrophobic contacts in some proteins at high urea concentrations and explain why the heat capacity signature (Δ C P ) of a compact denatured state can be similar to Δ C P values calculated by assuming an open random‐coil‐like unfolded state. Proteins 2002;49:560–566. © 2002 Wiley‐Liss, Inc.