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Keywords:

  • C[BOND]H…O hydrogen bond;
  • α-helix;
  • hydrogen bonding potentials;
  • solvent shielding;
  • side-chain conformational entropy;
  • helix propensity;
  • helix capping;
  • chain reversal motif

Abstract

A comprehensive database analysis of C[BOND]H…O hydrogen bonds in 3124 α-helices and their corresponding helix termini has been carried out from a nonredundant data set of high-resolution globular protein structures resolved at better than 2.0 Å in order to investigate their role in the helix, the important protein secondary structural element. The possible occurrence of 5 [RIGHTWARDS ARROW] 1 C[BOND]H…O hydrogen bond between the ith residue CH group and (i − 4)th residue C[DOUBLE BOND]O with C…O ≤ 3.8 Å is studied, considering as potential donors the main-chain Cα and the side-chain carbon atoms Cβ, Cγ, Cδ and Cϵ. Similar analysis has been carried out for 4 [RIGHTWARDS ARROW] 1 C[BOND]H…O hydrogen bonds, since the C[BOND]H…O hydrogen bonds found in helices are predominantly of type 5 [RIGHTWARDS ARROW] 1 or 4 [RIGHTWARDS ARROW] 1. A total of 17,367 (9310 of type 5 [RIGHTWARDS ARROW] 1 and 8057 of type 4 [RIGHTWARDS ARROW] 1) C[BOND]H…O hydrogen bonds are found to satisfy the selected criteria. The average stereochemical parameters for the data set suggest that the observed C[BOND]H…O hydrogen bonds are attractive interactions. Our analysis reveals that the Cγ and Cβ hydrogen atom(s) are frequently involved in such hydrogen bonds. A marked preference is noticed for aliphatic β-branched residue Ile to participate in 5 [RIGHTWARDS ARROW] 1 C[BOND]H…O hydrogen bonds involving methylene Cγ 1 atom as donor in α-helices. This may be an enthalpic compensation for the greater loss of side-chain conformational entropy for β-branched amino acids due to the constraint on side-chain torsion angle, namely, χ1, when they occur in helices. The preference of amino acids for 4 [RIGHTWARDS ARROW] 1 C[BOND]H…O hydrogen bonds is found to be more for Asp, Cys, and for aromatic residues Trp, Phe, and His. Interestingly, overall propensity for C[BOND]H…O hydrogen bonds shows that a majority of the helix favoring residues such as Met, Glu, Arg, Lys, Leu, and Gln, which also have large side-chains, prefer to be involved in such types of weak attractive interactions in helices. The amino acid side-chains that participate in C[BOND]H…O interactions are found to shield the acceptor carbonyl oxygen atom from the solvent. In addition, C[BOND]H…O hydrogen bonds are present along with helix stabilizing salt bridges. A novel helix terminating interaction motif, X-Gly with Gly at Ccap position having 5 [RIGHTWARDS ARROW] 1 Cα[BOND]H…O, and a chain reversal structural motif having 1 [RIGHTWARDS ARROW] 5 Cα-H…O have been identified and discussed. Our analysis highlights that a multitude of local C[BOND]H…O hydrogen bonds formed by a variety of amino acid side-chains and Cα hydrogen atoms occur in helices and more so at the helix termini. It may be surmised that the main-chain Cα and the side-chain CH that participate in C[BOND]H…O hydrogen bonds collectively augment the cohesive energy and thereby contribute together with the classical N[BOND]H…O hydrogen bonds and other interactions to the overall stability of helix and therefore of proteins. Proteins 2004. © 2004 Wiley-Liss, Inc.