Role of backbone solvation in determining thermodynamic β propensities of the amino acids

There is a paradox concerning the 0 propensities of the amino acids: the amino acids with the highest 0 propensities such as valine and isoleucine have the highest tendency to desolvate the peptide backbone, which should result in a loss of stability. Nevertheless, backbone solvation, calculated as electrostatic solvation free energy (ESF), is highly correlated with mutant stability in the zinc-finger system studied by Kim and Berg [Kim, C. A. & Berg, J. M. (1993) Nature (London) 362, 267-270], and valine and isoleucine are among the most stabilizing amino acids. This inverse correlation between stability and ESF can be explained, because the mutant ESF differences in the unfolded protein are larger than in the native protein. Consequently, mutations such as Ala to Val destabilize the unfolded form more than the native protein. By comparing mutant DeltaESF values in isolated beta-strands versus beta-sheets, we conclude that amino adds with high 0 propensities should exert their stabilizing effects at early stages in folding, This deduction agrees with the studies by Clarke and coworkers [Lorch, M., Mason, J. M., Clarke, A. R. & Parker, M. J. (1999) Biochemistry 38,1377-1385, and Lorch, M., Mason, J. M., Sessions, R. B. & Clarke, A. R. (2000) Biochemistry 39,3480-3485] of the thermodynamics of folding of the beta-sheet protein CD2.d1.