Explore the species variation of TTR mediated thyroid disruption A molecular dynamics simulation
Thyroid disrupting chemicals (TDCs) are a variety of environmental xenobiotics that can potentially alter the structure or function of the thyroid gland, interfere with TH signaling and subsequently disrupt the homeostasis of the thyroid hormone (TH) system. Exposures to TDCs may induce significant disorders in vital physiological processes in human and wildlife, including macronutrient metabolism, energy balance, brain development, and reproduction. Transthyretin (TTR) is a conserved serum transport protein expressed across species, including Human (Homo Sapiens) and Gilthead Sea bream (Sparus Aurata). The protein is responsible for delivering the TH hormones 3,3',5-triiodo-L-thyronine (T3) and L-thyroxine (T4) from the thyroid gland to target tissues. TTR has been reported as a molecular target of TDCs, including per and polyfluoroalkyl substances (PFASs) and hydroxylated polychlorinated biphenyls (OH-PCBs). In silico models provides high throughput and cost-efficient approaches for identifying the most hazardous compounds in risk assessment processes. In this study, we aim at exploring the variations on disruptions effects of TDC targeting both human and sea bream TTR via in vitro affinity measurement, crystallizing of the TDCs-TTR complex structures and molecular dynamics (MD) simulations. In the initial step, we determined the X-ray crystallographic structures of human and Gilthead Sea bream TTR in complex with several representative TDCs. MD simulations will be performed based on these new crystallographic structures to give insights into ligand-protein binding conformations and reveal their interactions at the atomic level. Ligand binding free energy will be estimated using free energy perturbation theory (FEP) and molecular mechanics-generalized Born surface area (MM-GBSA). The binding free energy will be further decomposed onto residues that interacts with the ligands to identify the different patterns in ligand-TTR interactions between human and Sea bream. In the final step, we will summarize structure-activity relationship (SAR) for the TDCs targeting both human and sea bream TTR,which will enable us to have better knowledge of important structural motifs for the ligand-TTR recognitions across these two species. The outcomes of this study will improve our understandings of the variations on toxicities of TDCs across species. Understanding disruption mechanism at the molecular level might be able to provide guidance for designing compounds that avoid thyroid disruption effects. More importantly, this study will initiate the discussions whether fish is an optimal choice of animal models for assessing the toxicities of TDCs and estimating their adverse effects on human.