A Comprehensive Analysis of Anion-Quadrupole Interactions in Protein Structures.

Abstract

The edgewise interactions of anions with phenylalanine (Phe) aromatic rings in proteins, known as anion-quadrupole interactions, have been well studied. However, the anion-quadrupole interactions of the tyrosine (Tyr) and tryptophan (Trp) rings have been less well studied, probably because these have been considered weaker than interactions of anions hydrogen bonded to Trp/Tyr side chains. Distinguishing such hydrogen bonding interactions, we comprehensively surveyed the edgewise interactions of certain anions (aspartate, glutamate, and phosphate) with Trp, Tyr, and Phe rings in high-resolution, nonredundant protein single chains and interfaces (protein-protein, DNA/RNA-protein, and membrane-protein). Trp/Tyr anion-quadrupole interactions are common, with Trp showing the highest propensity and average interaction energy for this type of interaction. The energy of an anion-quadrupole interaction (-15.0 to 0.0 kcal/mol, based on quantum mechanical calculations) depends not only on the interaction geometry but also on the ring atom. The phosphate anions at DNA/RNA-protein interfaces interact with aromatic residues with energies comparable to that of aspartate/glutamate anion-quadrupole interactions. At DNA-protein interfaces, the frequency of aromatic ring participation in anion-quadrupole interactions is comparable to that of positive charge participation in salt bridges, suggesting an underappreciated role for anion-quadrupole interactions at DNA-protein (or membrane-protein) interfaces. Although less frequent than salt bridges in single-chain proteins, we observed highly conserved anion-quadrupole interactions in the structures of remote homologues, and evolutionary covariance-based residue contact score predictions suggest that conserved anion-quadrupole interacting pairs, like salt bridges, contribute to polypeptide folding, stability, and recognition.