Origin of the neighboring residue effect on peptide backbone conformation.

Unfolded peptides in water have some residual structure that may be important in the folding process, and the nature of the residual structure is currently of much interest. There is a neighboring residue effect on backbone conformation, discovered in 1997 from measurements of (3)J(HN alpha) coupling constants. The neighboring residue effect appears also in the "coil library" of Protein Data Bank structures of residues not in alpha-helix and not in beta-structure. When a neighboring residue (i - 1 or i + 1) belongs to class L (aromatic and beta-branched amino acids, FHITVWY) rather than class S (all others, G and P excluded), then the backbone angle of residue i is more negative for essentially all amino acids. Calculated values of peptide solvation (electrostatic solvation free energy, ESF) predict basic properties of the neighboring residue effect. We show that L amino acids reduce the solvation of neighboring peptide groups more than S amino acids. When tripeptides from the coil library are excised to allow solvation, the central residues have more negative values of <phi> but less negative values of <ESF> with L than with S neighbors. The coil library values of <(3)J(HN alpha)>, which vary strikingly among the amino acids, are correlated with the neighboring residue effect seen by ESF. Moreover, values for the "blocking effect" of side chains on the hydrogen exchange rates of peptide NH protons are correlated with ESF values.