arXiv subjects

Ricardo Ugarte

Publications and source records attributed to Ricardo Ugarte.

3 recordsLinked to original sources

arXiv2022

FMO Study of the Interaction Energy between Human Estrogen Receptor $α$ and Selected Ligands

Fragment molecular orbital (FMO) calculations were performed in aqueous media which allowed us to obtain the interaction energy between the human estrogen receptor $α$ ligand-binding domain (ER) and the selected ligands (L): 17$β$-estradiol (E2), 17$α$-estradiol (17$α$-E2), estriol (E3), genistein (GNT), diethylstilbestrol (DES), bisphenol A (BPA), bisphenol AF (BPAF), hydroxychlor (HPTE) and methoxychlor (DMDT). These calculations were carried out on representative structures of L-ER complexes obtained from molecular dynamics simulations. The MP2/6-31G(d) L-ER FMO interaction energy in kcal/mol is as follows: E3 (-100.1) < GNT (-95.8) < E2 (-88.5) < BPA (-84.7) < DES (-82.6) < BPAF (-80.6) < 17$α$-E2 (-78.7) < HPTE (-75.9) < DMDT (-46.3) The central hydrophobic core of the ligands interacts attractively with several apolar amino acid residues of ER. Glu 353 and His 524 interacts strongly with most ligands through a hydrogen bond with the hydroxyl group of the phenol A-ring and the terminal hydroxylated ring, respectively. Water molecules were found at the binding site of receptor. In our model systems we have demonstrated what is generally observed in ligand-receptor complexes: the steric and chemical complementarity of the groups on the ligand and binding site surfaces.

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arXiv2022

FMO Interaction Energy between 17$β$-Estradiol, 17$α$-Estradiol and Human Estrogen Receptor $α$

The estrogen receptor is a nuclear hormone receptor activated by the natural steroid hormone 17$β$-estradiol (E2). Fragment molecular orbital (FMO) calculations were performed which allowed us to obtain the interaction energy ($E_{int}$) between E2, 17$α$-estradiol (17$α$-E2) and the human estrogen receptor $α$ 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$α$-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$α$-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.

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arXiv2019

Approximate calculation of the binding energy between 17$β$-estradiol and human estrogen receptor alpha

Estrogen receptors (ERs) are a group of proteins activated by 17$β$-estradiol. The endocrine-disrupting chemicals (EDCs) mimic estrogen action by bind directly to the ligand binding domain of ER. From this perspective, ER represent a good model for identifying and assessing the health risk of potential EDCs. This ability is best reflected by the ligand-ER binding energy. Multilayer fragment molecular orbital (MFMO) calculations were performed which allowed us to obtain the binding energy using a calculation scheme that considers the molecular interactions that occur on the following model systems: the bound and free receptor, 17$β$-estradiol and a water cluster. The bound and free receptor and 17$β$-estradiol were surrounded by a water shell containing the same number of molecules as the water cluster. The structures required for MFMO calculations were obtained from molecular dynamics simulations and cluster analysis. Attractive dispersion interactions were observed between 17$β$-estradiol and the binding site hydrophobic residues. In addition, strong electrostatic interactions were found between 17$β$-estradiol and the following charged/polarized residues: Glu 353, His 524 and Arg 394. The FMO2-RHF/STO-3G:MP2/6-31G(d) weighted binding energy was of -67.2 kcal/mol. We hope that the model developed in this study can be useful for identifying and assessing the health risk of potential EDCs.

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