title: A Statistical Survey on the Binding Constants of Covalently Bound Protein-Ligand Complexes.
abstract: We have conducted a statistical survey to compare the binding constants of covalently and noncovalently bound protein-ligand complexes as two groups. In our study, a total of 1602 complexes formed between various types of proteins and small-molecule ligands were selected from the PDBbind database (version 2008), all of which had high-resolution three-dimensional structures and reliable experimentally measured binding constants. These complexes were further classified as 79 covalent complexes, 131 Zn-containing complexes, and 1392 noncovalent complexes. Covalent complexes formed through reversible mechanisms are found to be associated with higher binding constants than noncovalent complexes. Two-sample T-test indicates that the difference is statistically significant. The advantage, however, is only modest (<20 folds). The same trend is also observed on a set of covalent and noncovalent complexes formed by thrombin. Our results indicate that reversible covalent bonding formed between protein and ligand will not automatically lead to a much tighter binding in general. Thus, our survey does not provide any supporting evidence for Houk's hypothesis which states that covalent bonding formed between enzyme and transition state accounts for the extraordinary proficiency of enzymes.
authors.affiliation: State Key Laboratory of Bioorganic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China, P. R. tel: 86-21-54925128.
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioorganic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China, P. R. tel: 86-21-54925128.
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Bioorganic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China, P. R. tel: 86-21-54925128.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioorganic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China, P. R. tel: 86-21-54925128.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioorganic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China, P. R. tel: 86-21-54925128.
authors.forename: Jiajie
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioorganic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China, P. R. tel: 86-21-54925128. wangrx@mail.sioc.ac.cn.
authors.forename: Renxiao
authors.initials: R
authors.lastname: Wang
keywords: Binding constant; Covalent binding; Drug design; Enzyme proficiency; Molecular modeling; PDBbind; Protein-ligand complex