Strong and weak hydrogen bonds in the protein-ligand interface

The characteristics of N-H center dot center dot center dot O, O-H center dot center dot center dot O, and C-H center dot center dot center dot O hydrogen bonds and other weak intermolecular interactions are analyzed in a large and diverse group of 251 protein-ligand complexes using a new computer program that was developed in-house for this purpose. The interactions examined in the present study are those which occur in the active sites, defined here as a sphere of 10 angstrom radius around the ligand. Notably, N-H center dot center dot center dot O and O-H center dot center dot center dot O bonds tend towards linearity. Multifurcated interactions are especially common, especially multifureated acceptors, and the average degree of furcation is 2.6 hydrogen bonds per furcated acceptor. A significant aspect of this study is that we have been able to assess the reliability of hydrogen bond geometry as a function of crystallographic resolution. Thresholds of 2.3 and 2.0 angstrom are established for strong and weak hydrogen bonds, below which hydrogen bond geometries may be safely considered for detailed analysis. Interactions involving water as donor or acceptor, and C-H center dot center dot center dot O bonds with Gly and Tyr as donors are ubiquitous in the active site. A similar trend was observed in an external test set of 233 protein-ligand complexes belonging to the kinase family. Weaker interactions like X-H center dot center dot center dot pi (X = C, N, O) and those involving halogen atoms as electrophiles or nucleophiles have also been studied. We conclude that the strong and weak hydrogen bonds are ubiquitous in protein-ligand recognition, and that with suitable computational tools very large numbers of strong and weak intermolecular interactions in the ligand-protein interface may be analyzed reliably. Results confirm earlier trends reported previously by us but the extended nature of the present data set mean that the observed trends are more reliable. Proteins 2007;67:128-141. (c) 2007 Wiley-Liss, Inc.