title: A survey of aspartate-phenylalanine and glutamate-phenylalanine interactions in the protein data bank: searching for anion-π pairs.
abstract: Protein structures are stabilized using noncovalent interactions. In addition to the traditional noncovalent interactions, newer types of interactions are thought to be present in proteins. One such interaction, an anion-π pair, in which the positively charged edge of an aromatic ring interacts with an anion, forming a favorable anion-quadrupole interaction, has been previously proposed [Jackson, M. R., et al. (2007) J. Phys. Chem. B111, 8242-8249]. To study the role of anion-π interactions in stabilizing protein structure, we analyzed pairwise interactions between phenylalanine (Phe) and the anionic amino acids, aspartate (Asp) and glutamate (Glu). Particular emphasis was focused on identification of Phe-Asp or -Glu pairs separated by less than 7 Å in the high-resolution, nonredundant Protein Data Bank. Simplifying Phe to benzene and Asp or Glu to formate molecules facilitated in silico analysis of the pairs. Kitaura-Morokuma energy calculations were performed on roughly 19000 benzene-formate pairs and the resulting energies analyzed as a function of distance and angle. Edgewise interactions typically produced strongly stabilizing interaction energies (-2 to -7.3 kcal/mol), while interactions involving the ring face resulted in weakly stabilizing to repulsive interaction energies. The strongest, most stabilizing interactions were identified as preferentially occurring in buried residues. Anion-π pairs are found throughout protein structures, in helices as well as β strands. Numerous pairs also had nearby cation-π interactions as well as potential π-π stacking. While more than 1000 structures did not contain an anion-π pair, the 3134 remaining structures contained approximately 2.6 anion-π pairs per protein, suggesting it is a reasonably common motif that could contribute to the overall structural stability of a protein.
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996-0840, United States.
authors.forename: Vivek
authors.initials: V
authors.lastname: Philip
authors.forename: Jason
authors.initials: J
authors.lastname: Harris
authors.forename: Rachel
authors.initials: R
authors.lastname: Adams
authors.forename: Don
authors.initials: D
authors.lastname: Nguyen
authors.forename: Jeremy
authors.initials: J
authors.lastname: Spiers
authors.forename: Jerome
authors.initials: J
authors.lastname: Baudry
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Howell
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hinde
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D030562:Databases, Protein; D004735:Energy Transfer; D018698:Glutamic Acid / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D010649:Phenylalanine / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D011506:Proteins; D001224:Aspartic Acid; D018698:Glutamic Acid; D010649:Phenylalanine