J. Chem. Theory Comput., 2008, 4, 1959–1973.

Zhiguo Liu, Guitao Wang, Zhanting Li and Renxiao Wang*

 

Abstract. We have conducted potential of mean force (PMF) analyses to derive the geometrical parameters of various types of hydrogen bonds on protein−ligand binding interface. Our PMF analyses are based on a set of 4535 high-quality protein−ligand complex structures, which are compiled through a systematic mining of the entire Protein Data Bank. Hydrogen bond donor and acceptor atoms are classified into several basic types. Both distance- and angle-dependent statistical potentials are derived for each donor−acceptor pair, from which distance and angle cutoffs are obtained in an objective, unambiguous manner. These donor−acceptor pairs are also studied by quantum mechanics (QM) calculations at the MP2/6−311++G** level on model molecules. Comparison of the outcomes of PMF analyses and QM calculations suggests that QM calculation may serve as an alternative approach for characterizing hydrogen bond geometry. Both of our PMF analyses and QM calculations indicate that C−H···O hydrogen bonds are relatively weak as compared to common hydrogen bonds formed between nitrogen and oxygen atoms. A survey on the protein−ligand complex structures in our data set has revealed that Cα-H···O hydrogen bonds observed in protein−ligand binding are frequently accompanied by bifurcate N−H···O hydrogen bonds. Thus, the Cα-H···O hydrogen bonds in such cases would better be interpreted as secondary interactions.