Stacking and T-shape competition in aromatic-aromatic amino acid interactions

Area of Science:

• Computational chemistry
• Biophysics
• Structural biology

Background:

• Aromatic amino acids, phenylalanine (Phe) and tyrosine (Tyr), are crucial for protein structure and function.
• Understanding their interactions, such as stacking and T-shaped arrangements, is key to predicting protein folding and stability.

Purpose of the Study:

• To investigate the free energy landscapes of interacting Phe-Phe, Phe-Tyr, and Tyr-Tyr complexes.
• To determine the preferred interaction modes (stacked vs. T-shaped) in various solvents and under different geometric constraints.
• To compare simulation results with experimental protein structures to understand residue interaction patterns in vivo.

Main Methods:

• Molecular dynamics (MD) simulations to calculate the potential of mean force (PMF).
• Free energy surface calculations to analyze stacking and T-shape conformations.
• Analysis of a large experimental protein structure database (2396 structures).
• Voronoi polyhedron analysis for spatial arrangement of residues.

Main Results:

• Stacked structures are generally favored for Phe-Phe, Phe-Tyr, and Tyr-Tyr complexes across solvents, except for Tyr-Tyr in carbon tetrachloride where T-shaped structures are also significant.
• Short C(alpha)-C(alpha) distances favor stacked arrangements, while large distances favor T-shaped structures.
• Experimental data shows Tyr-Tyr interactions predominantly on protein surfaces, while Phe-Phe and Phe-Tyr interactions are more common in hydrophobic cores.
• Protein analysis confirms that proximal aromatic residues are mainly stacked, and distal ones are T-shaped.

Conclusions:

• Solvent polarity and residue type significantly influence aromatic amino acid interaction geometries.
• Distance between C(alpha) atoms is a critical factor determining stacked versus T-shaped interactions.
• Simulation findings align with experimental observations of aromatic residue positioning within protein structures, differentiating core and surface interactions.