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

Abstract

A survey of 322 proteins showed that the short polar (SP) side chains of four residues, Thr, Ser, Asp, and Asn, have a very strong tendency to form hydrogen 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 stability by a hydrogen bond with the amide of the N3 or N2 residue is well established. 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 backbone carbonyl for the same hydrogen-bonding partner (i.e., the backbone amide) and thus SP residues tend to break backbone carbonyl-amide hydrogen bonds. The proposition that this is the origin for the low propensities of SP residues in the middle of alpha helices (relative to those of nonpolar residues) was tested. The combined effects of restricting side-chain rotamer conformations (documented by Creamer and Rose, Proc Acad Sci USA, 1992;89:5937-5941; Proteins, 1994;19:85-97) and excluding side- chain to backbone hydrogen bonds by the helix were quantitatively analyzed. These were found to correlate 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 loss of side-chain conformational entropy needs to be considered).

Structure of CrgA, a cell division structural and regulatory protein fromMycobacterium tuberculosis, in lipid bilayers

“…In addition, the side chain of Asn74 reaches across the interhelical interface to hydrogen bond with the backbone carbonyl of Leu53. This variety of side-chain-backbone hydrogen bonding is typical of polar residues in TM helices (56).…”

Mimicry by asx‐ and ST‐turns of the four main types of β‐turn in proteins

“…However, the chemical properties of the four residues (D, N, S, and T) are not dissimilar and they exhibit a tendency in such situations to substitute each other over evolutionary time (Vijayakumar et al 1999;Wan and Milner-White 1999b).…”

“…We refer to these collectively as ST-turns (Wan and Milner-White 1999b). Sequence comparisons of homologous proteins (Vijayakumar et al 1999;Wan and Milner-White 1999b) show that, within and between asx-and ST-turns, the four residues in question often substitute each other.…”

Mutational Analysis of Different Regions in the Coxsackievirus 2B Protein

“…Further analysis demonstrated the preference for the small polar Asp and Asn residues at amino acid positions 61 and 62 over the larger Glu and Gln residues. Both Asp and Asn residues, and not Glu and Gln, have been implicated in the formation of reverse turns, possibly because these amino acids easily form hydrogen bonds with the peptide backbone (44,45). Together, these data indicate that the hydrophilic region between HR1 and HR2 indeed facilitates a reverse turn, and they suggest that 2B adopts a helix-loop-helix structure, a commonly found structural feature in membrane-active proteins (29,46).…”

“…20). The 2B protein contains two hydrophobic regions, designated HR1 (amino acids [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] and HR2 (amino acids 63-80), of which the first is predicted to form a cationic amphipathic ␣-helix (21,22). The amphipathic ␣-helix displays characteristics typical for the group of lytic polypeptides, which may build membrane-integral pores upon the formation of multimeric transmembrane complexes (23)(24)(25).…”