title: Conformational Preferences of π-π Stacking Between Ligand and Protein, Analysis Derived from Crystal Structure Data Geometric Preference of π-π Interaction.
abstract: π-π Interaction is a direct attractive non-covalent interaction between aromatic moieties, playing an important role in DNA stabilization, drug intercalation, etc. Aromatic rings interact through several different conformations including face-to-face, T-shaped, and offset stacked conformation. Previous quantum calculations indicated that T-shaped and offset stacked conformations are preferred for their smaller electron repulsions. However, substitution group on aromatic ring could have a great impact on π-π interaction by changing electron repulsion force between two rings. To investigate π-π interaction between ligand and aromatic side chain of protein, Brookhaven Protein Data Bank was analyzed. We extracted isolated dimer pairs with the aim of excluding multiple π-π stacking effects and found that T-shaped conformation is prevalent among aromatic interaction between phenyl ring of ligand and protein, which corresponds with the phenomenon of Phe-Phe interactions in small peptide. Specifically, for the non-substitution model, both Phe-Phe and Phenyl-Phe exhibit a favored T-shaped conformation whose dihedral angle is around 50°-70° and centroid distance is between 5.0 and 5.6 Å. However, it could be changed by substituent effect. The hydroxyl group could contact in the case of Tyr-Tyr pairs, while they point away from phenyl plane in Phe-Tyr pairs.
authors.affiliation: Department of Chemistry, China Novartis Institutes for BioMedical Research Co. Ltd., Shanghai, 201203, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: College of Life Science and Biotechnology and State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, 200240, China.
authors.forename: Jue
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Life Science and Biotechnology and State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, 200240, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gu
authors.affiliation: College of Life Science and Biotechnology and State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University, Shanghai, 200240, China.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Chemistry, China Novartis Institutes for BioMedical Research Co. Ltd., Shanghai, 201203, China.
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 200032, China. wfu@fudan.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.affiliation: Department of Chemistry, China Novartis Institutes for BioMedical Research Co. Ltd., Shanghai, 201203, China. zhengtian.yu@novartis.com.
authors.forename: Zhengtian
authors.initials: Z
authors.lastname: Yu
mesh_terms: D018360:Crystallography, X-Ray; D030562:Databases, Protein; D004151:Dipeptides / Q000737:chemistry; D008024:Ligands; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D055672:Static Electricity
chemical_list: D004151:Dipeptides; D008024:Ligands; D011506:Proteins; C026650:phenylalanylphenylalanine
keywords: Geometric preference; Multiple π–π interaction; Parallel conformation; Substitution effect; T-shaped conformation; π–π interaction