FMO Interaction Energy between 17$\beta$-Estradiol, 17$\alpha$-Estradiol and Human Estrogen Receptor $\alpha$

TL;DR

This study uses fragment molecular orbital calculations to analyze the interaction energies of estradiol isomers with the human estrogen receptor alpha, revealing differences in binding and dynamics that influence biological activity.

Contribution

It provides detailed interaction energy data and dynamic insights into how different estradiol isomers bind to and affect the estrogen receptor alpha.

Findings

E2 has stronger interaction energy than 17α-E2

Water molecules and electrostatic interactions are crucial for binding

E2's motion adapts to the receptor, unlike 17α-E2

Abstract

The estrogen receptor is a nuclear hormone receptor activated by the natural steroid hormone 17$\beta$-estradiol (E2). Fragment molecular orbital (FMO) calculations were performed which allowed us to obtain the interaction energy ($E_{int}$) between E2, 17$\alpha$-estradiol (17$\alpha$-E2) and the human estrogen receptor $\alpha$ ligand-binding domain. In aqueous media the MP2/6-31G(d) $E_{int}$ was of -88.52 kcal/mol for E2 and -78.73 kcal/mol for 17$\alpha$-E2. Attractive dispersion interactions were observed between ligands and all surrounding hydrophobic residues. Water molecules were found at the binding site and strong attractive electrostatic interactions were observed between the ligands and the Glu 353 and His 524 residues. The essential dynamics revealed that E2 adapts to the binding site and its motion, in a sense, synchronizes with the whole receptor; while 17$\alpha$-E2, with its motion of greater amplitude compared to E2, disturbs the binding site. Perhaps this feature of the normal substrate is a necessary condition for biological function. Another important requirement relates to the number of water molecules at the binding site. Therefore, negative values in $E_{int}$ is a necessary but not sufficient condition since, it is also necessary to consider the conformers population that fulfill all the requirements that ensure a biological response.