Linear and nonlinear optical properties of a series of bis(E-dimesitylborylethenyl)-substituted arenes have been modeled by high-level computational protocols. The former compounds show a remarkable interest as infrared two-photon absorbers and hence may be used in the field of optical active and smart materials or for energy storage purposes. Excited state topologies, absorption and emission spectra, excited state metrics, natural transition orbitals and two-photon absorption cross-section of a series of chromophores have been computed by means of density functional theory (DFT) and timedependent DFT (TD-DFT). An extended benchmark test on the performance of different functionals had been performed. Dynamic and vibronic effects on absorption and emission spectra have been taken into account by sampling the conformational space by means of Wigner distribution and the former have been evidenced as rather important in order to recover absorption maxima and spectral band shape. Important infrared two photon absorption cross sections involving transitions to the second excited state have been observed. In particular, thiophene bridges have been evidenced as the most beneficial to increase TPA efficiency leading to cross-section exceeding 1000 GM.
Per-
and polyfluoroalkyl substances (PFASs) are a class of environmentally
persistent industrial compounds that disrupt various metabolic pathways.
Among the protein receptors to which PFASs bind, the human pregnane
X receptor (hPXR) is found to be a host for a variety of long- and
short-chain PFASs that lead to its overactivation. Overactivation
of hPXR is linked to potential endocrine disruption, oxidative stress,
hepatic steatosis, and adverse drug interactions. In this study, molecular
dynamics (MD) is used to study the binding between hPXR and a number
of PFAS compounds, including alternatives whose activity on hPXR has
not been experimentally tested. This is the first-time MD is used
to study the interactions between PFASs and hPXR, showing how relative
binding free energies of PFASs relate to hPXR agonism. Binding free
energy calculations, hydrogen bond analysis, per-residue decomposition
calculations, and alanine scanning studies are done to provide further
insight. Activities on hPXR for several short-chain and alternative
PFAS compounds to long-chain PFASs that have yet to be reported will
also be considered. These short-chain and alternative species include
perfluorobutane sulfonic acid (PFBS), Gen-X (trade name for 2,3,3,3-tetrafluoro-2-heptafluoropropoxy
propanoic acid), ADONA (trade name for 4,8-dioxa-3H-perfluorononanoic acid), and 6:2 fluorotelomer carboxylic acid (6:2
FTCA). The study shows key aspects of PFAS recognition on the hPXR,
the link between PFAS binding to hPXR and the hPXR activity change
observed upon the PFAS exposure, and the potential effects of alternative
PFASs on hPXR activity.
Peroxisome proliferator
receptor gamma (PPARγ), a type II
nuclear receptor, fundamental in the regulation of genes, glucose
metabolism, and insulin sensitization has been shown to be impacted
by per- and poly-fluoroalkyl substances (PFASs). To consider the influence
of PFASs upon PPARγ, the molecular interactions of 27 PFASs
have been investigated. Two binding sites have been identified on
the PPARγ homodimer structure: the dimer pocket and the ligand
binding pocket, the former has never been studied prior. Molecular
dynamics calculations were performed to gain insights about PFASs-PPARγ
binding and the role of acidic and basic residues. The electrostatic
interactions for acidic and basic residues far from the binding site
were probed, together with their effect on PPARγ recognition.
Short-range electrostatic and van der Waals interactions with nearby
residues and their influence on binding energies were investigated.
As the negative effects of perfluorooctane sulfonate acid were previously
shown to be alleviated by one of its natural ligands,
l
-carnitine,
here, the utility of
l
-carnitine as a possible inhibitor
for other PFASs has been considered. A comparison of the binding patterns
of
l
-carnitine and PFASs provides insights toward mitigation
strategies for PFASs.
In this effort in the SAMPL6 host-guest binding challenge, a combination of molecular dynamics and quantum mechanical methods were used to blindly predict the host-guest binding free energies of a series of cucurbit[8]uril (CB8), octa-acid (OA), and tetramethyl octa-acid (TEMOA) hosts bound to various guest molecules in aqueous solution. Poses for host-guest systems were generated via molecular dynamics (MD) simulations and clustering analyses. The binding free energies for the structures obtained via cluster analyses of MD trajectories were calculated using the MMPBSA method and density functional theory (DFT) with the inclusion of Grimme's dispersion correction, an implicit solvation model to model the aqueous solution, and the resolution-of-the-identity (RI) approximation (MMPBSA, RI-B3PW91-D3, and RI-B3PW91, respectively). Among these three methods tested, the results for OA and TEMOA systems showed MMPBSA and RI-B3PW91-D3 methods can be used to qualitatively rank binding energies of small molecules with an overbinding by 7 and 37 kcal/mol respectively, and RI-B3PW91 gave the poorest quality results, indicating the importance of dispersion correction for the binding free energy calculations. Due to the complexity of the CB8 systems, all of the methods tested show poor correlation with the experimental results. Other quantum mechanical approaches used for the calculation of binding free energies included DFT without the RI approximation, utilizing truncated basis sets to reduce the computational cost (memory, disk space, CPU time), and a corrected dielectric constant to account for ionic strength within the implicit solvation model.
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