Moving Domain Qm/Mm Methods for Determination of Interactions between Human Estrogen Receptor Alpha and Endocrine Disrupters
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Date
2019-05
Authors
Omolloh, George Ochieng
Journal Title
Journal ISSN
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Publisher
Kenyatta University
Abstract
Human Estrogen Receptor alpha (hERa), a fundamental protein responsible for the detection of the sex hormone estrogen and regulating downstream gene expression is, usually, activated upon binding of a natural hormone. The hERa has flexibility to interact with and its functioning interfered with by many synthetic and natural chemicals, referred to as endocrine disruptive chemicals (EDCs). Malfunctioned estrogen receptor pathways have been indicted for causing breast cancer. In silico screening of a series of small molecules for endocrine disrupting capacity based on their interaction with the Human Estrogen Receptor alpha (hERα) was conducted to determine whether they would constitute a risk factor in breast cancer incidence. The force field polarization model, Moving Domain Quantum Mechanics/Molecular Mechanics (MoDQ3M), was used to describe the electric fields and electronic polarization effects inside the hERα protein. Molecular dynamics on the wildtype, polarized proteins, and in silico mutated proteins were conducted for five nanoseconds on both the agonist and antagonist poses using Desmond engine from DE Shaw research. Docking was performed using Glide as implemented in Schrodinger 2015.1 suite. In-depth analyses were carried out in order to understand the underlying molecular mechanism using techniques including force field polarization, molecular dynamics, ligand-protein residue interaction and free energy landscape analysis. These showed that the mutated residues, N537Y and N532D, changed the overall electrostatic environment of the system along with the ligand-protein interactions. Mutation on two residues were carried out in silico, and the results were compared between the wild type and mutant for both the agonist (PDB ID: 2B1Z) and antagonist (PDB ID: 3ERT). The mutation of N537Y on the agonist and N532D on the antagonist within the ligand binding domain of the protein altered the interaction of the top ranked EDC compounds giving an MM-GBSA binding energy of –5.531 kcal/mol and –8.047 kcal/mol, better than that of the wild type for the antagonist. Glide docking studies gave top-ranked EDCs as DES, Genistein, Nonylphenol-9, DDE, BPA with glide scores (kcal/mol) of -10.332, -11.127, -8.627, -8.735, -9.007, respectively, on the agonist and -10.459, -10.119, -8.612, -8.507, -9.988, respectively, on the antagonist. Similar EDCs ranks were also realized for the mutants. It was also realized that Genistein, Oxybenzone, Vinclozolin, E216, DDE, Nonylphenol-9, and DES were more stable in the active form (higher occupancy averages) than in the inactive configuration showing the probability of activation of the protein receptor. The insights from this study could be of great relevance while designing new drugs for the treatment of breast cancer. Design would have to ensure stability in the antagonist more than the agonist and the same time counter the effect of mutation on the antagonist system. It is suggested that products that lead to exposure to Genistein, Oxybenzone, Vinclozolin, E216, DDE, Nonylphenol-9, and DES should be avoided as much as possible because of their possible effects on the protein receptor.
Description
A Thesis Submitted in Partial Fulfillment of the Requirements for the Award of the Degree of Master of Science in the School of Pure and Applied Sciences of Kenyatta University