Lone pair ··· π interactions between water oxygens and aromatic residues: Quantum chemical studies based on high‐resolution protein structures and model compounds

Abstract

The p electron cloud of aromatic centers is known to be involved in several noncovalent interactions such as CAHÁÁÁp, OAHÁÁÁp, and pÁÁÁp interactions in biomolecules. Lone-pair (lp) ÁÁÁ p 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 Å ) 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 lpÁÁÁp interactions between water oxygen and aromatic residues. Quantum mechanical calculations at MP2/6-31111G(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 MP2/6-31111G(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 lpÁÁÁp 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.

Why pyridine containing pyrido[2,3-d]pyrimidin-7-ones selectively inhibit CDK4 than CDK2: Insights from molecular dynamics simulation

“….pi) interactions involving hydrogen atoms of water and pi electron cloud (aromatic rings) have been investigated [48]. Recently, Sankararamakrishnan and group have reported the possibility of even lone pairÁÁÁpi interactions between water oxygens and aromatic residues [49]. It is proposed that the flipped Tyr17 CDK4/CDK4-17 could possibly attain stability by such type of interactions.…”

Direct observation of hydrogen atom dynamics and interactions by ultrahigh resolution neutron protein crystallography

“…5C). The oxygen of W1023 is 3.78 Å from the center of the ring, farther than the 3.5 Å distance suggested for an interaction between an O lone pair and a delocalized π system (34). The O─H…π interaction is important for a wide variety of molecular recognition events, such as drug-receptor interactions and hydration of nucleic acids.…”

Directionality and site selectivity of N⋯Cl halogen bonding in two azaaromatic chloride crystals

“…In the previous literature [46][47][48][49][50], the theoretical values of the strength of lone pairÁ Á Áp interaction are no less than À5.45 kcal/mol, the theoretical values of the strength of p-p stack between parallel displaced phenyl rings are À0.8 $ À10.46 kcal/ mol, and the experimental and theoretical values of the interaction energy of CÀHÁ Á ÁO hydrogen bonding are À0.77 $ À2.72 kcal/mol. Consequently, the strengths of the NÁ Á ÁCl halogen bonding in the crystal structures 1 and 2 are comparable to those of lone pairÁ Á Áp interaction, p-p stack and CÀHÁ Á ÁO hydrogen bonding.…”