title: Structure-Based Design of a Br Halogen Bond at the Complex Interface of the Human Placental HtrA1 PDZ Domain with Its Heptapeptide Ligand.
abstract: The shock-induced serine protease HtrA1 is a potential regulator of human placenta development during pregnancy. The protein contains a functional PDZ domain that has been solved in complex with a phage display-derived heptapeptide: Asp-6 Ser-5 Arg-4 Ile-3 Trp-2 Trp-1 Val0 . In this study, a rationally designed halogen bond was introduced to the domain-peptide complex based on its NMR structure in solution. We computationally compared the stabilization energies and hindrance effects due to the presence of different halogens X (X = F, Cl, Br, or I), using a hybrid quantum mechanics/molecular mechanics (QM/MM) approach, and found that the Br atom could considerably promote the peptide binding free energy (ΔΔG = -5.2 kcal/mol). Fluorescence assays confirmed that the peptide affinity to the HtrA1 PDZ domain was improved by approximately sevenfold upon bromination. Structural analysis identified a geometrically perfect halogen bond between the Br atom of the peptide Trp-1 residue and the carbonyl O atom of the HtrA1 Ile385 residue, with a bond length and an interaction energy of d = 3.20 Å and ΔE = -3.7 kcal/mol, respectively.
authors.affiliation: Catheter Room, Affiliated Hospital of Weifang Medical University, Weifang, China.
authors.forename: Shuo-Fen
authors.initials: SF
authors.lastname: Dou
authors.affiliation: Department of Obstetrics, Affiliated Hospital of Weifang Medical University, Weifang, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Obstetrics, Affiliated Hospital of Weifang Medical University, Weifang, China.
authors.forename: Tong-Mei
authors.initials: TM
authors.lastname: Cao
authors.affiliation: Department of Obstetrics, Affiliated Hospital of Weifang Medical University, Weifang, China.
authors.forename: Qing-Li
authors.initials: QL
authors.lastname: Wen
authors.affiliation: Department of Obstetrics, Affiliated Hospital of Weifang Medical University, Weifang, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Obstetrics, Affiliated Hospital of Weifang Medical University, Weifang, China.
authors.forename: Qing-Chun
authors.initials: QC
authors.lastname: Shao
mesh_terms: D001966:Bromine / Q000737:chemistry; D005260:Female; D006219:Halogens / Q000737:chemistry*; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D008024:Ligands; D009842:Oligopeptides / Q000737:chemistry*; D054731:PDZ Domains; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D011485:Protein Binding; D011789:Quantum Theory; D012697:Serine Endopeptidases / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D006219:Halogens; D008024:Ligands; D009842:Oligopeptides; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases; D001966:Bromine
keywords: Halogen bond; HtrA1; Peptide; Placenta; Pregnancy