Conformational Preferences of ππ Stacking Between Ligand and Protein, Analysis Derived from Crystal Structure Data Geometric Preference of ππ Interaction

  • Yuan Zhao
  • Jue Li
  • Hui Gu
  • Dongqing Wei
  • Yao-chang Xu
  • Wei FuEmail author
  • Zhengtian YuEmail author
Original Research Article


ππ 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 ππ interaction by changing electron repulsion force between two rings. To investigate ππ 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 ππ 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.


ππ interaction Multiple ππ interaction Parallel conformation T-shaped conformation Substitution effect Geometric preference 



We are grateful to Dr. En Li of China Novartis for his support and encouragement. Financial support from the Educational Office of Novartis Institutes for BioMedical Research is gratefully acknowledged. We also wish to thank Timothy Yu for his re-checking of the data reported in some of the Tables during his internship day at Fudan University.


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Copyright information

© International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of ChemistryChina Novartis Institutes for BioMedical Research Co. Ltd.ShanghaiChina
  2. 2.College of Life Science and Biotechnology and State Key Laboratory of Microbial MetabolismShanghai Jiao Tong UniversityShanghaiChina
  3. 3.Department of Medicinal Chemistry, School of PharmacyFudan UniversityShanghaiChina

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