Hydrogen Bonds in Proteins: Role and Strength

Abstract

Hydrogen bonds provide most of the directional interactions that underpin protein folding, protein structure and molecular recognition. The core of most protein structures is composed of secondary structures such as α helix and β sheet. This satisfies the hydrogen‐bonding potential between main chain carbonyl oxygen and amide nitrogen buried in the hydrophobic core of the protein. Hydrogen bonding between a protein and its ligands (protein, nucleic acid, substrate, effector or inhibitor) provides a directionality and specificity of interaction that is a fundamental aspect of molecular recognition. The energetics and kinetics of hydrogen bonding therefore need to be optimal to allow the rapid sampling and kinetics of folding, conferring stability to the protein structure and providing the specificity required for selective macromolecular interactions.

Key concepts:

  • A hydrogen bond is formed by the interaction of a hydrogen atom that is covalently bonded to an electronegative atom (donor) with another electronegative atom (acceptor).

  • Hydrogen bonding confers rigidity to the protein structure and specificity to intermolecular interactions.

  • The accepted (and most frequently observed) geometry for a hydrogen bond is a distance of less than 2.5 Å (1.9 Å) between hydrogen and the acceptor and a donor‐hydrogen‐acceptor angle of between 90° and 180° (160°).

  • During protein folding, the burial of hydrophobic side‐chains requires intramolecular hydrogen bonds to be formed between the main chain polar groups.

  • The most stable conformations of polypeptide chains that maximize intrachain hydrogen‐bonding potential are α helices and β sheets.

  • Specificity in molecular recognition is driven by the interaction of complementary hydrogen‐bonding groups on interacting surfaces.

Keywords: hydrogen bond; protein structure; protein stability; molecular recognition; secondary structure

Figure 1.

(a) Schematic representation of the geometry of a hydrogen bond. On the left is the definition of geometry when proton positions are defined; on the right when they are not. D, donor atom; A, acceptor and H, hydrogen. (b) Distribution of geometry for hydrogen bonds in α helices. The plots show approximate distributions (number of occurrences, N) for the angle at the carbonyl oxygen (O) acceptor, distance between the carbonyl oxygen acceptor and amide proton (H) donor and the angle at the amide proton donor and carbonyl oxygen acceptor (Baker and Hubbard, ).

Figure 2.

An α helix from the structure of oxygenated human myoglobin (Phillips, ). (a) The complete helix with main chain atoms shown as liquorice bonds (nitrogen blue, oxygen red and carbon green), side‐chains shown as balls and sticks in black, and hydrogen bonds as white dashed lines. (b) Detail of the N‐terminal region of the helix, marked B in (a). The asterisk marks the serine oxygen that caps the helix. (c) Detail of the C‐terminal portion of the helix, including water positions observed in the structure. The asterisk highlights the carboxyl oxygen making a bifurcated hydrogen bond. Coordinates from Protein Data Bank entry 1MBO.

Figure 3.

A β sheet from the structure of thioredoxin (Weichsel et al., ), showing just the main chain atoms as liquorice bonds (nitrogen blue, oxygen red and carbon green) and hydrogen bonds as white dashed lines. The arrows show the direction of the polypeptide chain, emphasizing that both parallel and antiparallel strands are present in this structure. Coordinates from Protein Data Bank entry 1ERT.

Figure 4.

Side‐by‐side stereo figure showing the details of the interaction between a portion of an inhibitor binding to the cellulase, Cel5A (Varrot et al., ). This structure is of sufficient resolution (0.95 Å) so that proton positions can be modelled; for clarity, they are shown only on the ligand. Water molecules are shown as blue spheres and hydrogen bonds as white dashed lines. The nitrogen atoms are in blue, hydrogen grey and oxygen red, with the carbon atoms of the protein in green and ligand orange. The asterisk shows the site of linkage to the rest of the inhibitor. Details about A, B and C are discussed in the text.

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Further Reading

Dunitz JD (1995) Win some, lose some: enthalpy–entropy compensation in weak intermolecular interactions. Chemistry and Biology 2: 709–712.

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Karshikoff A (2006) Non‐covalent Interactions in Proteins. London: Imperial College Press.

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Ming‐Hong Hao (2006) Theoretical calculation of hydrogen‐bonding strength for drug molecules. Journal of Chemical Theory and Computation 2(3): 863–872.

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Hubbard, Roderick E, and Kamran Haider, Muhammad(Feb 2010) Hydrogen Bonds in Proteins: Role and Strength. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0003011.pub2]