N-H···O, O-H···O, and C-H···O hydrogen bonds in protein-ligand complexes: strong and weak interactions in molecular recognition

Sarkhel, Sanjay ; Desiraju, Gautam R. (2004) N-H···O, O-H···O, and C-H···O hydrogen bonds in protein-ligand complexes: strong and weak interactions in molecular recognition Proteins: Structure, Function, and Bioinformatics, 54 (2). pp. 247-259. ISSN 0887-3585

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Official URL: http://onlinelibrary.wiley.com/doi/10.1002/prot.10...

Related URL: http://dx.doi.org/10.1002/prot.10567


The characteristics of N-H···O, O-H···O, and C-H···O hydrogen bonds are examined in a group of 28 high-resolution crystal structures of protein-ligand complexes from the Protein Data Bank and compared with interactions found in small-molecule crystal structures from the Cambridge Structural Database. It is found that both strong and weak hydrogen bonds are involved in ligand binding. Because of the prevalence of multifurcation, the restrictive geometrical criteria set up for hydrogen bonds in small-molecule crystal structures may need to be relaxed in macromolecular structures. For example, there are definite deviations from linearity for the hydrogen bonds in protein-ligand complexes. The formation of C-H···O hydrogen bonds is influenced by the activation of the CaH atoms and by the flexibility of the side-chain atoms. In contrast to small-molecule structures, anticooperative geometries are common in the macromolecular structures studied here, and there is a gradual lengthening as the extent of furcation increases. C-H···O bonds formed by Gly, Phe, and Tyr residues are noteworthy. The numbers of hydrogen bond donors and acceptors agree with Lipinski's "rule of five"that predicts drug-like properties. Hydrogen bonds formed by water are also seen to be relevant in ligand binding. Ligand C-H···Ow interactions are abundant when compared to N-H···Ow and O-H···Ow. This suggests that ligands prefer to use their stronger hydrogen bond capabilities for use with the protein residues, leaving the weaker interactions to bind with water. In summary, the interplay between strong and weak interactions in ligand binding possibly leads to a satisfactory enthalpy-entropy balance. The implications of these results to crystallographic refinement and molecular dynamics software are discussed.

Item Type:Article
Source:Copyright of this article belongs to John Wiley and Sons.
Keywords:Intermolecular Interaction; Enthalpy-entropy; Protein Data Bank; Cambridge Structural Database; Multifurcation; Water
ID Code:10752
Deposited On:09 Nov 2010 05:00
Last Modified:30 May 2011 09:29

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