A Comprehensive Analysis of Anion-Quadrupole Interactions in Protein Structures

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Anion-quadrupole interactions with phenylalanine (Phe) rings are well-established.
• Interactions involving tyrosine (Tyr) and tryptophan (Trp) rings are less understood, often overshadowed by hydrogen bonding.
• Previous studies have underestimated the prevalence and importance of anion-quadrupole interactions with Trp and Tyr residues.

Purpose of the Study:

• To comprehensively survey and characterize anion-quadrupole interactions involving Phe, Tyr, and Trp rings.
• To investigate these interactions across various protein contexts: single chains, protein-protein, DNA/RNA-protein, and membrane-protein interfaces.
• To compare the energetic contributions and conservation patterns of anion-quadrupole interactions with those of salt bridges.

Main Methods:

• Analysis of high-resolution, nonredundant protein structures.
• Systematic survey of interactions between specific anions (aspartate, glutamate, phosphate) and aromatic residues (Phe, Tyr, Trp).
• Quantum mechanical calculations to determine interaction energies.

Main Results:

• Anion-quadrupole interactions with Trp and Tyr rings are common, with Trp exhibiting the highest propensity and average interaction energy.
• Interaction energy is influenced by geometry and the specific aromatic ring atom.
• Phosphate anions at DNA/RNA-protein interfaces show interaction energies comparable to aspartate/glutamate.
• At DNA-protein interfaces, anion-quadrupole interactions are as frequent as salt bridges involving positively charged residues.
• Highly conserved anion-quadrupole interactions were observed in remote homologues, suggesting functional importance.

Conclusions:

• Anion-quadrupole interactions involving Trp and Tyr are prevalent and energetically significant, especially at protein-nucleic acid and membrane interfaces.
• These interactions are comparable in frequency and energy to salt bridges at certain interfaces, highlighting their underappreciated role.
• Conserved anion-quadrupole interactions contribute to protein folding, stability, and molecular recognition, similar to salt bridges.