Combined quantum mechanics/molecular mechanics (QM/MM) methods to understand the charge density distribution of estrogens in the active site of estrogen receptors.

The ligand binding to protein and host-guest interactions are ubiquitous for molecular recognition. In drug design, the ligand binding to the active site of proteins is influenced by the charge density distribution and the electrostatic interactions of ligands and the nearby amino acids of the protein. The charge density analyses of ligand-protein complexes need accurate positions of hydrogen atoms and their valence electron distribution and the fine structure of proteins. Such information cannot be obtained from the conventional protein X-ray crystallography analysis in the resolution range of 1.5 to 3.5 Å. This can be realized from QM/MM based structure and charge density analysis of estrogens with the estrogen receptor. The charge density properties such as electron density, Laplacian of electron density and electrostatic properties of estrogens in the presence of active site amino acid residues have been determined and compared with the isolated estrogen molecules from theory and experimental. The present study reveals the chemical bonding nature of estrogen molecules and the strength of the intermolecular interactions in the active site of estrogen receptor, and also the importance of π⋯π interactions between the estrogens and Phe404 amino acid residue and protonation state of His524 amino acid residue have been identified using electrostatic potential maps. The difference in the electrostatic potential map of estrogens displays the hormone dependent actions of estrogen receptor. This method is very helpful to derive the charge density distribution of macromolecules to understand their biological recognition and interactions.