CIS-TRANSISOMERIZATION AT PROLINE - DESOLVATION AND ITS CONSEQUENCES FOR PROTEIN FOLDING

Peptide bonds to the nitrogen atom of proline undergo cis/trans isomerization slowly, in a process that limits the rates of refolding of many denatured proteins in vitro. At 333 K, acetylproline N-methylamide undergoes cis-to-trans isomerization 46-fold more rapidly in toluene than in water, consistent with the idea that the transition state for isomerization is less polar than that for either the cis or the trans isomer. The catalytic action of peptidyl-prolyl isomerases, whose active sites appear to be relatively nonpolar, may thus be explained at least in part by desolvation. These results imply that protein folding is most likely to be impeded by isomerization at exposed proline residues that remain exposed to solvent in the transition state for refolding, whereas peptidyl-prolyl linkages in a protein's interior, or at a nonpolar protein-protein interface, probably undergo rapid isomerization without the assistance of an external catalyst. © 1992.