Hydrogen bonds between short polar side chains and peptide backbone: Prevalence in proteins and effects on helix-forming propensities

A survey of 322 proteins showed that the short polar (SP) side chains of fo ur residues, Thr, Ser, Asp, and Asn, have a very strong tendency to form hy drogen bonds with neighboring backbone amides. Specifically, 32% of Thr, 29 % of Ser, 26% of Asp, and 19% of Asn engage in such hydrogen bonds. When an SP residue caps the N terminal of a helix, the contribution to helix stabi lity by a hydrogen bond with the amide of the N3 or N2 residue is well esta blished. When an SP residue is in the middle of a helix, the side chain is unlikely to form hydrogen bonds with neighboring backbone amides for steric and geometric reasons. In essence the SP side chain competes with the back bone carbonyl for the same hydrogen-bonding partner (i.e., the backbone ami de) and thus SP residues tend to break backbone carbonyl-amide hydrogen bon ds. The proposition that this is the origin for the low propensities of SP residues in the middle of ex helices (relative to those of nonpolar residue s) was tested. The combined effects of restricting side-chain rotamer confo rmations (documented by Creamer and Rose, Proc Acad Sci USA, 1992;89:5937-5 941; Proteins, 1994;19:85-97) and excluding side- chain to backbone hydroge n bonds by the helix were quantitatively analyzed. These were found to corr elate strongly with four experimentally determined scales of helix-forming propensities. The correlation coefficients ranged from 0.72 to 0.87, which are comparable to those found for nonpolar residues (for which only the los s of side-chain conformational entropy needs to be considered). Proteins 19 99;34:497-507. (C) 1999 Wiley-Liss, Inc.