Mechanistic aspects of reactive metabolite formation in clomethiazole catalyzed biotransformation by cytochrome P450 enzymes

Organic & Biomolecular Chemistry, Journal Year: 2023, Volume and Issue: 21(35), P. 7158 - 7172

Published: Jan. 1, 2023

Clomethiazole is likely to contribute the mechanism-based inactivation of P450 by forming clomethiazole epoxide or hydroxyl adducts, rather than further metabolization adverse reactive metabolites in its catalyzed biotransformation pathways.

Language: Английский

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Multilevel Framework for Analysis of Protein Folding Involving Disulfide Bond Formation

The Journal of Physical Chemistry B, Journal Year: 2024, Volume and Issue: 128(13), P. 3145 - 3156

Published: March 21, 2024

In this study, a three-layered multicenter ONIOM approach is implemented to characterize the naive folding pathway of bovine pancreatic trypsin inhibitor (BPTI). Each layer represents distinct level theory, where initial layer, encompassing entire protein, modeled by general all-atom force-field GFN-FF. An intermediate electronic structure consisting three fragments introduced with state-of-the-art semiempirical tight-binding method GFN2-xTB. Higher accuracy, specifically addressing breaking and formation disulfide bonds, achieved at innermost using composite DFT r2SCAN-3c. Our analysis sheds light on structural stability BPTI, particularly significance interlinking bonds. The accuracy efficiency QM/SQM/MM are benchmarked oxidative cystine. For relative stabilities investigated through calculation free energy contributions for selected intermediates, focusing impact bond. results highlight intricate trade-off between computational cost, demonstrating that provides well-balanced comprehensive solution describe effects in biomolecular systems. We conclude multiscale landscape exploration robust methodology study intriguing biological targets.

Language: Английский

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Autobench V1.0: Benchmarking Automation for Electronic Structure Calculations

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(8), P. 3322 - 3331

Published: March 27, 2024

This work reports on new software for automatic conformer energy benchmarking calculations flexible molecules. The workflow consists of four parts: conformational search, preoptimization, optimization, and frequency at a higher level last using several theoretical levels. was written to be user-friendly versatile used by nonexperts in computational chemistry. Any levels available either Gaussian 16 or ORCA 5 may applied the study. will automatically run search deal with conformers that converge same minimum those show negative frequency. At end workflow, user have mean absolute deviations most accurate method/DFT functional basis set comparison benchmark molecular system interest. Case examples are given paper help users get insight into software's main features.

Language: Английский

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Automated and Efficient Generation of General Molecular Aggregate Structures

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 62(4)

Published: Nov. 17, 2022

Abstract Modeling intermolecular interactions of complex non‐covalent structures is important in many areas chemistry. To facilitate the generation reasonable dimer, oligomer, and general aggregate geometries, we introduce an automated computational interaction site screening (aISS) workflow. This easy‐to‐use tool combines a genetic algorithm employing force‐field xTB‐IFF for initial search steps with GFN‐FF semi‐empirical GFN2‐xTB method geometry optimizations. Compared alternative CREST program, aISS yields similar results but computer time savings 1–3 orders magnitude. allows treatment systems thousands atoms composed elements up to radon, e.g ., metal‐organic complexes, or even polyhedra zeolite cut‐outs which were not accessible before. Moreover, can identify reactive sites provides options like site‐directed (user‐guided) screening.

Language: Английский

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Benchmark Study on the Calculation of ¹¹⁹Sn NMR Chemical Shifts

Inorganic Chemistry, Journal Year: 2022, Volume and Issue: 61(9), P. 3903 - 3917

Published: Feb. 18, 2022

A new benchmark set termed SnS51 for assessing quantum chemical methods the computation of 119Sn NMR shifts is presented. It covers 51 unique a selection 50 tin compounds with diverse bonding motifs and ligands. The experimental reference data are in spectral range ±2500 ppm measured seven different solvents. Fifteen common density functional approximations, two scalar- one spin-orbit relativistic approach assessed based on conformer ensembles generated using CREST/CENSO scheme state-of-the-art semiempirical (GFN2-xTB), force field (GFN-FF), composite DFT (r2SCAN-3c). Based results this study, method combinations SO-ZORA PBE0 or revPBE functionals generally recommended. Both yield mean absolute deviations from below 100 excellent linear regression determination coefficients ≤0.99. If calculations not affordable, use SR-ZORA B3LYP X2C ωB97X M06 may be considered to obtain qualitative predictions if no severe effects, example, due heavy nuclei containing ligands, expected. An empirical scaling correction demonstrated applicable further improvement, respective parameters given. Conformational effects studied detail but mostly found small. However, specific cases when ligand sphere differs substantially between conformers, can change by up several hundred ppm.

Language: Английский

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