International
Tables for
Crystallography
Volume F
Crystallography of biological macromolecules
Edited by M. G. Rossmann and E. Arnold

International Tables for Crystallography (2006). Vol. F, ch. 22.2, pp. 551-552   | 1 | 2 |

Section 22.2.7. Non-conventional hydrogen bonds

E. N. Bakera*

aSchool of Biological Sciences, University of Auckland, Private Bag 92-109, Auckland, New Zealand
Correspondence e-mail: ted.baker@auckland.ac.nz

22.2.7. Non-conventional hydrogen bonds

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The vast majority of hydrogen bonds in biological macromolecules involve nitrogen and oxygen donors exclusively. Nevertheless, several other interactions have all the characteristics of hydrogen bonds and clearly contribute to structure and stability where they occur.

22.2.7.1. C—H···O hydrogen bonds

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Sutor (1962[link]) first summarized evidence for C—H···O hydrogen bonds following earlier suggestions by Pauling (1960[link]), and current evidence has been nicely summarized in several recent articles (Derewenda et al., 1995[link]; Wahl & Sundaralingam, 1997[link]). The energy of C—H···O hydrogen bonds has been generally estimated as ∼0.5 kcal mol−1 (about 10% of an N—H···O interaction) but may be higher, especially in hydrophobic environments. It also depends on the acidity of the C—H proton, with methylene (CH2) and methyne (CH) groups being most favourable.

A number of examples of C—H···O hydrogen bonds can be found in nucleic acid structures (Wahl & Sundaralingam, 1997[link]). The best known is that between the backbone O5′ oxygen and a purine C(8)—H or pyrimidine C(6)—H, when the bases are in the anti conformation. Another example is given by a U–U base pair, in which the two bases form a conventional N(3)—H···O(4) hydrogen bond and a C(5)—H···O hydrogen bond.

In proteins, two groups are regarded as being particularly significant (Derewenda et al., 1995[link]). These are the C[epsilon]H of His side chains and the methylene H atoms of the main-chain α-carbon atoms. C—H···O hydrogen bonds involving His side chains have been found for the active-site His residues of proteins of the lipase/esterase family and in other proteins (Derewenda et al., 1994[link]). The CαH atoms appear to provide much more widespread C—H···O hydrogen bonding, however, especially in β-sheets, where they are directed towards the `free' lone pairs of the main-chain C=O groups. C—H···O hydrogen bonds may thus play a previously unrecognised role in satisfying the hydrogen-bond potential of C=O groups. In general, Derewenda et al. (1995[link]) find a significant number of C···O contacts that meet the criteria for C—H···O hydrogen bonds; the H···O distance peaks at 2.45 Å (C···O 3.5 Å), which is less than the van der Waals distance of 2.7 Å, and the angles indicate that the H atoms are directed at the acceptor lone-pair orbitals.

22.2.7.2. Hydrogen bonds involving sulfur atoms

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Sulfur atoms are larger and have a more diffuse electron cloud than oxygen or nitrogen, but are nevertheless capable of participating in hydrogen bonds. Given that the radius of sulfur is ∼0.4 Å greater than that of oxygen, hydrogen bonds can be assumed if the distance H···S is less than ∼2.9 Å, or S···O(N) is less than ∼3.9 Å, providing the angular geometry is right. In proteins, the SH group of cysteine can be a hydrogen-bond acceptor or donor, whereas the sulfur atoms in disulfide bonds and in Met side chains can act only as acceptors.

The clearest example of hydrogen bonding involving Cys residues is given by the NH···S hydrogen bonds in Fe-S proteins (Adman et al., 1975[link]); here, peptide NH groups are oriented to point directly at the S atoms of metal-bound Cys residues, with H···S distances of 2.4–2.9 Å. Similar NH···S hydrogen bonds are found in blue copper proteins, involving the Cys ligands. In these cases, the cysteine sulfur is deprotonated and therefore more negative, making it a stronger hydrogen-bond acceptor, and it is likely that hydrogen bonding to cysteine S atoms is common. A large survey of Cys and Met side chains in proteins has given evidence of both N—H···S and S—H···O hydrogen bonds involving the SH groups of Cys side chains (Gregoret et al., 1991[link]). In particular, Cys residues in helices frequently hydrogen bond to the main-chain C=O group four residues back in the helix in [\hbox{SH}(n)\cdots\hbox{O}(n-4)] interactions analogous to those seen for Ser and Thr residues in helices. On the other hand, O—H···S or N—H···S hydrogen bonds to the S atoms of Met or half-cystine side chains, although they do exist, are rare (Gregoret et al., 1991[link]; Ippolito et al., 1990[link]).

22.2.7.3. Amino-aromatic hydrogen bonding

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Surveys of protein structures have shown that aromatic rings (of Trp, Tyr, or Phe) are frequently in close association with side-chain NH groups of Lys, Arg, Asn, Gln, or His (Burley & Petsko, 1986[link]). Energy calculations further suggest that where an N—H group, as donor, is directed towards the centre of an aromatic ring, as acceptor, a hydrogen-bonded interaction with an energy of ∼3 kcal mol−1 (about half that of a normal N—H···O or O—H···O hydrogen bond) can result (Levitt & Perutz, 1988[link]). Whether the close associations observed by Burley & Petsko can truly be regarded as hydrogen bonds has been controversial, however. Mitchell et al. (1994[link]) have analysed amino–aromatic interactions and shown that by far the most common form of association between sp2 nitrogen atoms and aromatic rings involves approximately plane-to-plane stacking, which cannot represent hydrogen bonding. There is still, however, a significant number of cases where the H atoms of N—H groups are directed towards aromatic rings, and these represent genuine hydrogen bonds (Mitchell et al., 1994[link]). It is clearly essential to consider the donor–acceptor geometry, both distances and angles, before assuming an amino–aromatic hydrogen bond; the N···ring distance should be less than ∼3.8 Å, and N—H··· C angle greater than 120°, where C is the ring centre (Mitchell et al., 1994[link]).

References

Adman, E., Watenpaugh, K. D. & Jensen, L. H. (1975). N—H···S hydrogen bonds in Peptococcus aerogenes ferredoxin, Clostridium pasteurianum rubredoxin and Chromatium high potential iron protein. Proc. Natl Acad. Sci. USA, 72, 4854–4858.Google Scholar
Baker, E. N. & Hubbard, R. E. (1984). Hydrogen bonding in globular proteins. Prog. Biophys. Mol. Biol. 44, 97–179.Google Scholar
Bordo, D. & Argos, P. (1994). The role of side-chain hydrogen bonds in the formation and stabilization of secondary structure in soluble proteins. J. Mol. Biol. 243, 504–519.Google Scholar
Burley, S. K. & Petsko, G. A. (1986). Amino–aromatic interactions in proteins. FEBS Lett. 203, 139–143.Google Scholar
Cate, J. H., Gooding, A. R., Podell, E., Zhou, K., Golden, B. L., Kundrot, C. E., Cech, T. R. & Doudna, J. A. (1996). Crystal structure of a group I ribozyme domain: principles of RNA packing. Science, 273, 1678–1685.Google Scholar
Derewenda, Z. S., Derewenda, U. & Kobos, P. (1994). (His)C[epsilon]—H···O=C< hydrogen bond in the active site of serine hydrolases. J. Mol. Biol. 241, 83–93.Google Scholar
Derewenda, Z. S., Lee, L. & Derewenda, U. (1995). The occurrence of C—H···O hydrogen bonds in proteins. J. Mol. Biol. 252, 248–262.Google Scholar
Gregoret, L. M., Rader, S. D., Fletterick, R. J. & Cohen, F. E. (1991). Hydrogen bonds involving sulfur atoms in proteins. Proteins Struct. Funct. Genet. 9, 99–107.Google Scholar
Ippolito, J. A., Alexander, R. S. & Christianson, D. W. (1990). Hydrogen bond stereochemistry in protein structure and function. J. Mol. Biol. 215, 457–471.Google Scholar
Levitt, M. & Perutz, M. F. (1988). Aromatic rings act as hydrogen bond acceptors. J. Mol. Biol. 201, 751–754.Google Scholar
McDonald, I. K. & Thornton, J. M. (1994a). Satisfying hydrogen bonding potential in proteins. J. Mol. Biol. 238, 777–793.Google Scholar
Mitchell, J. B. O., Nandi, C. L., McDonald, I. K., Thornton, J. M. & Price, S. L. (1994). Amino/aromatic interactions in proteins: is the evidence stacked against hydrogen bonding? J. Mol. Biol. 239, 315–331.Google Scholar
Pauling, L. (1960). The nature of the chemical bond, 3rd ed. Ithaca: Cornell University Press.Google Scholar
Sutor, D. J. (1962). The C—H···O hydrogen bond in crystals. Nature (London), 195, 68–69.Google Scholar
Wahl, M. C. & Sundaralingam, M. (1997). C—H···O hydrogen bonding in biology. Trends Biochem. Sci. 22, 97–102.Google Scholar








































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