Stacking and T-shape Competition in Aromatic−Aromatic Amino Acid Interactions

Abstract

The potential of mean force of interacting aromatic amino acids is calculated using molecular dynamics simulations. The free energy surface is determined in order to study stacking and T-shape competition for phenylalanine-phenylalanine (Phe-Phe), phenylalanine-tyrosine (Phe-Tyr), and tyrosine-tyrosine (Tyr-Tyr) complexes in vacuo, water, carbon tetrachloride, and methanol. Stacked structures are favored in all solvents with the exception of the Tyr-Tyr complex in carbon tetrachloride, where T-shaped structures are also important. The effect of anchoring the two alpha-carbons (C(alpha)) at selected distances is investigated. We find that short and large C(alpha)-C(alpha) distances favor stacked and T-shaped structures, respectively. We analyze a set of 2396 protein structures resolved experimentally. Comparison of theoretical free energies for the complexes to the experimental analogue shows that Tyr-Tyr interaction occurs mainly at the protein surface, while Phe-Tyr and Phe-Phe interactions are more frequent in the hydrophobic protein core. This is confirmed by the Voronoi polyhedron analysis on the database protein structures. As found from the free energy calculation, analysis of the protein database has shown that proximal and distal interacting aromatic residues are predominantly stacked and T-shaped, respectively.

The Low-Potency, Voltage-Dependent HERG Blocker Propafenone—Molecular Determinants and Drug Trapping

“…Each docking run was ranked by energy (see key at bottom) and defined by the number of HERG Tyr652 or Phe656 aromatic ring atoms within 4.5 Å of a propafenone aromatic ring atom. A distance cutoff of 4.5 Å was taken to be the maximum separation of aromatic ring atoms that give rise to energetically favorable -stacking interactions (McGaughey et al, 1998;Chelli et al, 2002). The maximum number of ring atoms per Tyr652 or Phe656 was taken to be 11 (all ring carbons and ring-bound atoms ortho-, meta-, or para-to the carbon atom linking the ring to the ␤ carbon of the side chain).…”

Oligomerization of the γ-Aminobutyric Acid Transporter-1 Is Driven by an Interplay of Polar and Hydrophobic Interactions in Transmembrane Helix II

“…-stacking), which supports transporter oligomerization and subsequent plasma membrane targeting. The phenol ring of tyrosine and the phenyl-side chain of phenylalanine have a propensity to interact with the planar hydrophobic moieties in a stacked or T-shaped conformation (26). These interactions between phenyls were shown to drive self-association of a transmembrane segment of IsK ion channel (27).…”

Crystal structures of a therapeutic single chain antibody in complex with two drugs of abuse—Methamphetamine and 3,4‐methylenedioxymethamphetamine

“…16 Molecular dynamics simulation calculations on model compounds indicate that one of the optimal geometries for aromatic residue pairs is a T-shaped arrangement where the edge of one ring points to the face of the other. 18 In this configuration, hydrogen atoms with partial positive charges on the edge of one ring can interact favorably with the pi electrons or the partially negatively charged carbons of the other ring. In the scFv6H4 crystal structures, the aromatic rings of METH and MDMA molecules are oriented nearly perpendicular to the benzene ring of TrpL91 and similarly the PheL96 side chain is almost orthogonal to the aromatic rings of METH and MDMA, indicating that the pairing interactions play an important role in binding.…”