title: Regulation of protein-ligand binding affinity by hydrogen bond pairing.
abstract: Hydrogen (H)-bonds potentiate diverse cellular functions by facilitating molecular interactions. The mechanism and the extent to which H-bonds regulate molecular interactions are a largely unresolved problem in biology because the H-bonding process continuously competes with bulk water. This interference may significantly alter our understanding of molecular function, for example, in the elucidation of the origin of enzymatic catalytic power. We advance this concept by showing that H-bonds regulate molecular interactions via a hitherto unappreciated donor-acceptor pairing mechanism that minimizes competition with water. On the basis of theoretical and experimental correlations between H-bond pairings and their effects on ligand binding affinity, we demonstrate that H-bonds enhance receptor-ligand interactions when both the donor and acceptor have either significantly stronger or significantly weaker H-bonding capabilities than the hydrogen and oxygen atoms in water. By contrast, mixed strong-weak H-bond pairings decrease ligand binding affinity due to interference with bulk water, offering mechanistic insight into why indiscriminate strengthening of receptor-ligand H-bonds correlates poorly with experimental binding affinity. Further support for the H-bond pairing principle is provided by the discovery and optimization of lead compounds targeting dietary melamine and Clostridium difficile toxins, which are not realized by traditional drug design methods. Synergistic H-bond pairings have therefore evolved in the natural design of high-affinity binding and provide a new conceptual framework to evaluate the H-bonding process in biological systems. Our findings may also guide wider applications of competing H-bond pairings in lead compound design and in determining the origin of enzymatic catalytic power.
authors.affiliation: Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Chemistry and Chemical Engineering College, Gannan Normal University, Ganzhou, Jiangxi 341000, P. R. China.
authors.forename: Deliang
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.; Texas Children's Microbiome Center, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Numan
authors.identifier: 0000-0002-3175-2382
authors.initials: N
authors.lastname: Oezguen
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.; Texas Children's Microbiome Center, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Petri
authors.identifier: 0000-0003-2516-766X
authors.initials: P
authors.lastname: Urvil
authors.affiliation: Echelon Biosciences Inc., Salt Lake City, UT 84108, USA.
authors.forename: Colin
authors.identifier: 0000-0002-9021-4533
authors.initials: C
authors.lastname: Ferguson
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Dann
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.; Texas Children's Microbiome Center, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Tor C
authors.initials: TC
authors.lastname: Savidge
mesh_terms: D015195:Drug Design; D006860:Hydrogen Bonding; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*
chemical_list: D008024:Ligands; D011506:Proteins
keywords: Binding affinity; Biological activity; Clostridium difficile toxin; Computational chemistry; Drug design; Enzyme catalysis; Hydrogen bond pairing; Hydrogen bonding capability; Hydrogen bonds