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Structure‐Based Design of a Br Halogen Bond at the Complex Interface of the Human Placental HtrA1 PDZ Domain with Its Heptapeptide Ligand
Author(s) -
Dou ShuoFen,
Liu Hong,
Cao TongMei,
Wen QingLi,
Li Jie,
Shao QingChun
Publication year - 2016
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201500466
Subject(s) - pdz domain , chemistry , peptide , stereochemistry , halogen bond , residue (chemistry) , molecular mechanics , peptide bond , ligand (biochemistry) , crystallography , molecular dynamics , hydrogen bond , molecule , computational chemistry , biochemistry , organic chemistry , receptor
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 Val 0 . 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 (ΔΔ G = −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 Δ E = −3.7 kcal/mol, respectively.