Cl–π interactions in protein–ligand complexes

Abstract

During systematic analysis of nonbonded contacts in protein-ligand complexes derived from crystal structures in the Protein Data Bank, Cl-p interactions have been found, not only in the well-documented serine proteases but also, to a lesser extent, in other proteins. From geometric analysis of such Cl-p interactions in the crystal structures, two distinct geometries were found: the ''edge-on'' approach of a Cl atom to a ring atom or C-C bond and the ''face-on'' approach toward the ring centroid with an average interatomic distance of 3.6 Å . High-level ab initio calculations using benzene-chlorohydrocarbon model systems elucidated that the calculated Cl-p interaction energy is À2.01 kcal/mol, and the dispersion force is the major source of attraction. We also discussed the geometric flexibility in Cl-p interactions and a relationship between the intensity of the p density in an aromatic ring and the interaction position of the Cl atom.

Strength and Character of R–X···π Interactions Involving Aromatic Amino Acid Sidechains in Protein-Ligand Complexes Derived from Crystal Structures in the Protein Data Bank

“…This is consistent with previous SAPT results on model R-X···benzene complexes [24,25] and with the results of Imai and coworkers [27], who used Morokuma decomposition and comparison of Hartree-Fock and MP2 results to investigate the origins of attraction in R-Cl···benzene complexes. SAPT dispersion components fall in the range between −3.35 kcal/mol and −4.29 kcal/mol, while the electrostatic term ranges from −1.05 kcal/mol and −1.86 kcal/mol.…”

“…In recent protein database (PDB) survey studies seeking to identify halogen bonds existing in protein-ligand complexes, R-X···π interactions have been found to be one of the most common types of halogen bonding motifs [9,[26][27][28]. Examples of R-X···π interactions that contribute to the stabilization of protein-ligand complexes are given in Figure 1.…”

Cl–π Interactions in Protein–Ligand Complexes

“…To determine the geometries of the interactions, the q angle of the Cl atom relative to the plane of the ring was measured as shown in Figure 1A. Details of the searching procedure have been reported in previous articles [1,8].…”

Substituent Effects on the Crystal Structures of Salts Prepared from (R)-2-Methoxy-2-(1-naphthyl)propanoic Acid and (R)-1-Arylethylamines

“…Kinbara et al reported that the para-chlorine substituent of the 1-(4-chlorophenyl)ethylammonium cation increases the positive charge of the meta-hydrogen atoms, effectively stabilizing the C-H•••π interaction [18]. In contrast, the chlorine atom of salt 9 did not show any short contacts (e.g., Cl•••Cl, Cl•••O, or Cl•••π interactions [22]). The same is true for the chlorine atom of salt 8 (see below).…”