Lone pair ... pi interactions between water oxygens and aromatic residues: quantum chemical studies based on high-resolution protein structures and model compounds

Abstract

The pi electron cloud of aromatic centers is known to be involved in several noncovalent interactions such as C--H...pi, O--H...pi, and pi...pi interactions in biomolecules. Lone-pair (lp) ... pi interactions have gained attention recently and their role in biomolecular structures is being recognized. In this article, we have carried out systematic analysis of high-resolution protein structures and identified more than 400 examples in which water oxygen atoms are in close contact (distance < 3.5 A) with the aromatic centers of aromatic residues. Three different methods were used to build hydrogen atoms and we used a consensus approach to find out potential candidates for lp...pi interactions between water oxygen and aromatic residues. Quantum mechanical calculations at MP2/6-311++G(d,p) level on model systems based on protein structures indicate that majority of the identified examples have energetically favorable interactions. The influence of water hydrogen atoms was investigated by sampling water orientations as a function of two parameters: distance from the aromatic center and the angle between the aromatic plane and the plane formed by the three water atoms. Intermolecular potential surfaces were constructed using six model compounds representing the four aromatic amino acids and 510 different water orientations for each model compound. Ab initio molecular orbital calculations at MP2/6-311++G(d,p) level show that the interaction energy is favorable even when hydrogen atoms are farthest from the aromatic plane while water oxygen is pointing toward the aromatic center. The strength of such interaction depends upon the distance of water hydrogen atoms from the aromatic substituents. Our calculations clearly show that the lp...pi interactions due to the close approach of water oxygen and aromatic center are influenced by the positions of water hydrogen atoms and the aromatic substituents.

Figure 1

(A) Geometrical parameters defining water oxygen - aromatic interactions. d is the distance between the water oxygen (Ow) and the aromatic center (AC). r gives a measure of displacement of Ow from AC. θ is the angle between Ow, AC and one of the aromatic carbons (CA). (B) The parameter δ is the angle rotated about an axis that is perpendicular to the sixfold/fivefold rotational axis of the aromatic ring. At δ = 0°, this axis along with H—O—H bisector axis and the sixfold/fivefold rotational axis of aromatic ring will be perpendicular to each other. At δ = 90°, the bisector will be collinear to the sixfold/fivefold rotational axis.

Figure 2

(A) Distribution of angle ‘θ’ for the 19 examples extracted from high-resolution protein structures in which water oxygen atom is likely to interact with the π-electron cloud of the aromatic ring. (B) B-factor analysis of aromatic residues and water molecules. Dark grey bar indicates the average B-factors of those aromatic residues or water molecules involved in lp···π interactions. Light grey bar represents the average B-factor values of all aromatic residues or all water molecules from the high-resolution protein structures.

Figure 3

Examples of lp···π interactions in high-resolution protein structures. The four-letter PDB code and the chain ID of each structure are shown on the upper right corner of each example. Each aromatic residue is identified with its one letter amino acid code and residue number. The participating water molecule is displayed with the number as given in the respective PDB file. The distance between the oxygen atom and the aromatic center is shown. The BSSE corrected energy along with the interplanar angle (δ) are also displayed. Among the InsightII-generated coordinates, (A) the least and (B) the most energetically favorable aromatic–water interactions are shown. (C) Water oxygen atom interacts strongly with the aromatic center of protonated imidazole. In this case, hydrogen coordinates were generated using GROMACS-OPLS. (D) An example in which the distance between the two water hydrogen atoms from the aromatic center differs by 0.88 Å (4.23 vs. 3.35 Å) is shown and the hydrogen coordinates in this case were generated using InsightII. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 4

Snapshots during the sampling of water orientations with respect to the aromatic plane. The interplanar angle δ, is changed in steps of 10°. δ is the angle between the aromatic plane and the plane formed by the three atoms of the water molecule [Fig. 1(B)]. In this rotation, both water hydrogen atoms are equally displaced away from the aromatic ring. Four orientations representing four different δ values are shown for a fixed d value of 3.4 Å. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 5

Contour diagrams showing the intermolecular potential surface for the systems: (A) Benzene–water, (B) Imidazole–water, (C) Indole 6-membered ring–water, (D) Indole 5-membered ring–water, (E) Phenol–water, and (F) Protonated imidazole–water. Intermolecular potential surfaces are color coded; the colors red, orange, yellow, cyan, dark blue, dark brown indicate increasing level of favorable nature of oxygen···aromatic interactions with red and dark brown at the two extremes. Grey regions indicate unfavorable interactions.