Cation-pi interactions in structural biology

Abstract

Cation-pi interactions in protein structures are identified and evaluated by using an energy-based criterion for selecting significant sidechain pairs. Cation-pi interactions are found to be common among structures in the Protein Data Bank, and it is clearly demonstrated that, when a cationic sidechain (Lys or Arg) is near an aromatic sidechain (Phe, Tyr, or Trp), the geometry is biased toward one that would experience a favorable cation-pi interaction. The sidechain of Arg is more likely than that of Lys to be in a cation-pi interaction. Among the aromatics, a strong bias toward Trp is clear, such that over one-fourth of all tryptophans in the data bank experience an energetically significant cation-pi interaction.

Figure 1

Plots of E_es vs. CP-corrected, HF/6–31G** binding energies for selected cation-π interactions. Correlation coefficients are 0.93 for Lys-Phe and 0.81 for Arg-Phe. Comparable plots are seen for Lys-Trp and Arg-Trp interactions. Three outliers are circled in the Arg-Phe plot. Inspection of these pairs reveals spurious close contacts, which lead to erroneously high energies in the HF calculations but not in the OPLS calculations (see text). Removing these points improves the correlation coefficient to 0.85.

Figure 2

Scatter plots from the analysis of all 323 single subunit proteins. In each case, the cation is Lys, and a circle denotes the location of the sidechain N in one particular pair. Pictures are projections of a 10- × 10- × 10-Å cube in A and a 7- × 7- × 7-Å cube in B and C. (A) All Lys-Phe interactions. The phenyl ring plus the β carbon are denoted by black lines. A red circle denotes an interaction that is an accepted cation-π interaction; a blue circle denotes an interacting pair; a white circle denotes a structure rejected by the gap criterion. In this projection view, a few open/blue circles are seen to lie over the ring, but they are too far “above” the ring to have a favorable cation-π interaction. (B) Cation-π interactions involving Lys and Phe (gray circles) or Tyr (red circles). Note clustering of Tyr interactions near the phenolic oxygen (larger, light red circle). (C) Top down projection of all Lys-Trp cation-π interactions. The indole N is a blue circle. Note the cluster of structures above the six-membered ring.

Figure 3

An example of a strong cation-π interaction in an α-helix (E_es = −4.2 kcal/mol). The plot was created by using molscript and raster3d (36, 37).

Figure 4

Cation-π interactions involving arginine. (Upper) Parallel and T-shaped geometries. (Lower) Variation in interplane angle.

Figure 5

Schematic view of model used to calculate the preferred location for lysine phenylalanine pairs. The excluded volume region represents the volume of benzene plus the volume unavailable to atoms of radius 1.7 Å. The cylinder is tangent to the benzene (radius = 4.8 Å), obtained by adding the radius of benzene (1.4 + 1.7 Å) and the radius of a neighboring carbon atom (1.7 Å). The shell is obtained by adding a constant radius of 2.8 Å—the diameter of a water molecule—to the excluded volume region. This view shows the only the top half of the excluded volume and has portions of the shell and cylinder removed for clarity.

Figure 6

A cluster of cation-π interactions from the protein glucoamylase (PDB ID code: 1GAI). The NH₃⁺ of the lysine (central blue sphere; Hs not shown) is surrounded by two tryptophans and two tyrosines that contribute −22 kcal/mol E_es. The figure was generated by using povchem (http://grserv.med.jhmi.edu/∼paul/PovChem.html) and povray (http://www.povray.org/). Gray, carbon; red, oxygen; blue, nitrogen.