Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ

Zhang, Lianying; Ren, Xiaomin; Wan, Bin; Guo, Liang-Hong

doi:10.1016/j.taap.2014.06.020

Cited by 98 publications

(136 citation statements)

References 45 publications

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“…Also PFuDA exhibited the strongest experimental binding affinity in the human PPARγ-LBD according to the study by Zhang et al. [13].…”

Section: Binding Mode Identification By Classical Molecular Dynamics mentioning

confidence: 67%

Prediction of Accurate Binding Modes using Combination of classical and accelerated Molecular dynamics and Free Energy Perturbation Calculations: An Application to Toxicity Studies

Fratev

Steinbrecher

Jónsdóttir³

2018

Preprint

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Estimating the correct binding modes of ligands in protein-ligand complexes is not only crucial in the drug discovery process, but also for elucidating potential toxicity mechanisms. In the current paper, we discuss and demonstrate a computational modelling protocol using the combination of docking, classical (cMD) and accelerated (aMD) molecular dynamics and free energy perturbation (FEP+ protocol) for identification of the binding modes of selected perfluorocarboxyl acids (PFCAs) in the PPARγ nuclear receptor.Initially, we employed both the regular and induced fit docking which failed to correctly predict the ligand binding modes and rank the compounds with respect to experimental free energies of binding, when they were docked into non-native X-ray structure. The cMD and aMD simulations identified the presence of multiple binding modes for these compounds, and the shorter chain PFCAs (C6-C8) continuously moved between a few energetically favourable binding conformations. These results demonstrate that the docking scoring function cannot rank compounds precisely in such cases, not due to its insufficiency, but because of the use of incorrect or only one unique bindings pose, neglecting the protein dynamics. Finally, based on MD predictions of binding conformations, the FEP+ sampling protocol was extended and then accurately reproduced experimental differences in the free energies.Thus, the preliminary MD simulations can also provide helpful information about correct set-up of the . 20, 2018; 2 FEP+ calculations. These results show that the PFCAs binding modes were accurately predicted and the FEP+ protocol can be used to estimate free energies of binding of flexible molecules outside of typical drug-like compounds. CC-BY-NC-ND4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/251058 doi: bioRxiv preprint first posted online Jan.Our in silico workflow revealed the main characteristics of the PFCAs, which are week PPARγ partial agonists and illustrated the importance of specific ligand-residue interactions within the LBD. This work also suggests a common workflow for identification of ligand binding modes, ligand-protein dynamics description and relative free energy calculations.

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“…Also PFuDA exhibited the strongest experimental binding affinity in the human PPARγ-LBD according to the study by Zhang et al. [13].…”

Section: Binding Mode Identification By Classical Molecular Dynamics mentioning

confidence: 67%

Prediction of Accurate Binding Modes using Combination of classical and accelerated Molecular dynamics and Free Energy Perturbation Calculations: An Application to Toxicity Studies

Fratev

Steinbrecher

Jónsdóttir³

2018

Preprint

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“…Experimental studies have shown that PFASs activate alpha- and gamma-peroxisome proliferator activated receptors, 8–10 which play key roles in lipid and carbohydrate metabolism, providing biological plausibility for PFAS-induced childhood obesity and insulin resistance. A human study in children and adolescents has reported cardiometabolic and renal effects of childhood PFASs exposure.…”

Section: Discussionmentioning

confidence: 99%

“…PFASs interact with alpha- and gamma-peroxisome proliferator activated receptors, which play key roles in lipid and carbohydrate metabolism. 8 In cell culture studies using the 3T3-L1 preadipocyte system, several PFASs altered gene expression associated with adipocyte differentiation and lipid metabolism, 9 and developmental PFAS exposures in mice have resulted in increased leptin and insulin levels in midlife. 10 Microvascular endothelial cell culture studies have shown that PFAS exposure increases reactive oxidative species and induces endothelial permeability, 11 which plays a critical role in ischemic renal injury.…”

Section: Introductionmentioning

confidence: 99%

Serum perfluoroalkyl substances in children exposed to the world trade center disaster

Trasande

Koshy

Gilbert

et al. 2017

Environmental Research

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The World Trade Center (WTC) disaster released large amounts of various chemical substances into the environment, including perfluoroalkyl substances (PFASs). Yet, no studies have examined exposures in children living or attending schools near the disaster site. We measured serum PFASs in WTC Health Registry (WTCHR) respondents who were ≤8 years of age on September 11, 2001 and a sociodemographically-matched comparison group. We also examined the relationship of PFASs levels with dust cloud exposure; home dust exposure, and with traumatic exposure, the latter to take into account differences related to possible mental health consequences and associated behavioral problems. Serum samples, collected between 2014 and 2016, were analyzed from 123 WTCHR participants and from 185 participants in the comparison group. In the WTCHR group, median perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) levels were 1.81 ng/mL and 3.72 ng/mL, respectively. Controlling for sex, caloric intake, race/ethnicity, and date of birth, significant increases among WTCHR participants compared with the matched comparison group were detected for perfluorohexanesulfonate (0.23 ng/mL increase or 0.24 log unit increase, p=0.006); PFOS (0.86 ng/mL increase or 0.16 log unit increase, p=0.011); PFOA (0.35 ng/mL increase or 0.18 log unit increase, p<0.001); perfluorononanoic acid (0.12 ng/mL increase or 0.17 log unit increase, p=0.003); perfluorodecanoic acid (0.06 ng/mL increase or 0.42 log unit increase, p<0.001); and perfluoroundecanoic acid (0.03 ng/mL increase or 0.32 log unit increase, p=0.019). Stronger associations were identified for home dust exposures and traumatic exposures than dust cloud. These findings highlight the importance of conducting longitudinal studies in this population to assess possible cardiometabolic and renal consequences related to these exposures.

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“…Current evidence suggests that PFASs interfere with important biological processes, specifically activation of alpha- and gamma-peroxisome proliferator activated receptors, 14 which play key roles in lipid and carbohydrate metabolism and are also involved in lipid transport, cholesterol synthesis, cell communication, inflammation and oxidative stress. 15,16 Human studies have shown a positive association between levels of PFASs and total and non-high-density cholesterol in the NHANES, despite the relatively low level of exposure.…”

Section: Introductionamentioning

confidence: 99%

Serum perfluoroalkyl substances and cardiometabolic consequences in adolescents exposed to the World Trade Center disaster and a matched comparison group

Koshy

Attinà

Ghassabian

et al. 2017

Environment International

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Background Large amounts of various chemical contaminants, including perfluoroalkyl substances (PFASs), were released at the time of the World Trade Center (WTC) disaster. Thousands of children who lived and/or attended school near the disaster site were exposed to these substances but few studies have examined the possible consequences related to these exposures. Objectives To examine the relationship of PFASs serum levels with cardiometabolic profile in children and adolescents enrolled in the World Trade Center Health Registry (WTCHR) and a matched comparison group. Methods We evaluated WTCHR enrollees who resided in New York City and were born between September 11, 1993 and September 10, 2001, and a matched comparison group consisting of individuals who were ineligible for WTCHR participation upon distance of their home, school or work from the WTC and lack of participation in rescue and recovery activities. Matching was based on date of birth, sex, race, ethnicity, and income. We assessed exposure to PFASs, as measured by serum levels and association with cardiometabolic profile as measured by arterial wall stiffness, body mass index, insulin resistance, fasting total cholesterol, HDL, LDL and triglycerides. Results A total of 402 participants completed the study and serum samples were analyzed from 308 participants, 123 in the WTCHR group and 185 in the comparison group. In multivariable regression analysis, after adjusting for relevant confounders, we observed a significant, positive association of perfluorooctanoic acid (PFOA) with triglycerides (beta coefficient = 0.14, 95% CI: 0.02, 0.27, 15.1 percent change), total cholesterol (beta coefficient = 0.09, 95% CI: 0.04, 0.14, 9.2 percent change), and LDL cholesterol (beta coefficient = 0.11, 95% CI: 0.03, 0.19, 11.5 percent change). Perfluorohexanesulfonic acid levels were associated with decreased insulin resistance (beta coefficient = −0.09, 95% CI: −0.18, −0.003, −8.6 percent change); PFOA and perfluorononanoic acid were associated with increased brachial artery distensibility. Conclusions This research adds to our knowledge of the physical health impacts in a large group of children exposed to the WTC disaster. Abnormal lipid levels in young adults might be an early marker of atherosclerosis and cardiovascular diseases and our findings highlight the importance of conducting longitudinal studies in this population.

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Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ

Cited by 98 publications

References 45 publications

Prediction of Accurate Binding Modes using Combination of classical and accelerated Molecular dynamics and Free Energy Perturbation Calculations: An Application to Toxicity Studies

Prediction of Accurate Binding Modes using Combination of classical and accelerated Molecular dynamics and Free Energy Perturbation Calculations: An Application to Toxicity Studies

Serum perfluoroalkyl substances in children exposed to the world trade center disaster

Serum perfluoroalkyl substances and cardiometabolic consequences in adolescents exposed to the World Trade Center disaster and a matched comparison group

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