molUP: A VMD plugin to handle QM and ONIOM calculations using the gaussian software

Fernandes, Henrique S.; Ramos, María J.; Cerqueira, Nuno M. F. S. A.

doi:10.1002/jcc.25189

Cited by 35 publications

(37 citation statements)

References 16 publications

(20 reference statements)

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“…This method has proved to deliver results that closely resemble those gathered with the canonical CCSD(T), at near DFT cost, and has been successfully applied in numerous chemistry/biochemistry‐related studies . The QM region and link‐atoms of each stationary point were isolated using the molUP plugin for VMD software and subsequently submitted to DLPNO‐CCSD(T) SP energy calculations using the ORCA software (version 4.0.1.2) . The latter were performed with the cc‐pVDZ and cc‐pVTZ basis sets, as well as with the cc‐pVDZ/C and the cc‐pVTZ/C correlation fitting basis sets, keeping the default DLPNO cutoff parameters.…”

Section: Methodsmentioning

confidence: 99%

Human Fatty Acid Synthase: A Computational Study of the Transfer of the Acyl Moieties from MAT to the ACP Domain

et al. 2019

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Human Fatty Acid Synthase (hFAS) is a multidomain enzyme responsible for the biosynthesis of saturated fatty acids, which are crucial for numerous biological processes. During the biosynthetic reaction, hFAS incorporates acetyl and malonyl moieties through the action of its malonyl‐acetyl transferase (MAT) domain. These precursor molecules are transferred from CoA to the acyl‐carrier protein (ACP) domain by a two‐stage ping‐pong catalytic mechanism. The first stage, during which the acyl moieties are relocated from CoA to the MAT domain, has been elucidated in a previous work of ours. In this study, we employ QM/MM calculations at the DLPNO‐CCSD(T)/CBS:AMBER level of theory to understand the catalytic machinery behind the transfer of the acyl moieties from MAT to the ACP domain. The results show that the acyl transfer to the ACP's phosphopantetheine (PNS) occurs in two sequential events: Step 3) asynchronous concerted reaction that combines the deprotonation of the PNS's thiol group and the nucleophilic attack on the acyl‐Ser581 ester carbon; Step 4) tetrahedral intermediate breakdown and regeneration of the catalytic Ser581/His683 dyad. The energy barriers of these two steps are inferior to those reported for the first catalytic stage, suggesting that the rate‐limiting step of the MAT mechanism lies on Stage 1, particularly on the concerted nucleophilic attack that starts the reaction. The oxyanion hole, formed by the backbone amines of Met499 and Leu582, was reported to transiently stabilize the tetrahedral intermediate and to play a favorable catalytic effect on the overall MAT reaction, particularly through the reduction of the energetic span. The knowledge gathered in this work complements previous experimental and theoretical studies and instigates further investigations that explore the therapeutic potential of hFAS.

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Section: Methodsmentioning

confidence: 99%

Human Fatty Acid Synthase: A Computational Study of the Transfer of the Acyl Moieties from MAT to the ACP Domain

et al. 2019

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“…The molUP plugin for VMD software [47] was used to generate the ORCA input files. The calculations were performed with the cc-pVDZ, cc-pVTZ, aug-cc-pVDZ, and aug-cc-pVTZ basis sets, as well as with the respective cc-pVDZ/C, cc-pVTZ/C, aug-cc-pVDZ/C, and aug-cc-pVTZ/C auxiliary basis sets.…”

Section: Dlpno-ccsd(t) and Dft Calculationsmentioning

confidence: 99%

Assessing the validity of DLPNO‐CCSD(T) in the calculation of activation and reaction energies of ubiquitous enzymatic reactions

2020

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The domain-based local pair natural orbital coupled-cluster with single, double, and perturbative triples excitation (DLPNO-CCSD(T)) method was employed to portray the activation and reaction energies of four ubiquitous enzymatic reactions, and its performance was confronted to CCSD(T)/complete basis set (CBS) to assess its accuracy and robustness in this specific field. The DLPNO-CCSD(T) results were also confronted to those of a set of density functionals (DFs) to understand the benefit of implementing this technique in enzymatic quantum mechanics/molecular mechanics (QM/MM) calculations as a second QM component, which is often treated with DF theory (DFT). On average, the DLPNO-CCSD(T)/aug-cc-pVTZ results were 0.51 kcalÁmol −1 apart from the canonic CCSD(T)/CBS, without noticeable biases toward any of the reactions under study. All DFs fell short to the DLPNO-CCSD(T), both in terms of accuracy and robustness, which suggests that this method is advantageous to characterize enzymatic reactions and that its use in QM/MM calculations, either alone or in conjugation with DFT, in a two-region QM layer (DLPNO-CCSD(T): DFT), should enhance the quality and faithfulness of the results.

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“…We used hydrogen atoms as link atoms to complete the valence of the bonds spanning between the two layers of our ONIOM QM/MM scheme. Atomic charges for all atoms were extracted from the parameter file used in the MD simulations with the VMD molUP plugin, developed in our research group. It included ff99SB charges for all amino acid residues and RESP charges (Merz‐Kollman, HF/‐631G(d)) for the individual ligands.…”

Section: Methodsmentioning

confidence: 99%

“…The VMD plug‐in molLUP was used to setup and analyze all the results that were generated in the QM/MM calculations …”

Section: Methodsmentioning

confidence: 99%

Solving the Catalytic Mechanism of Tryptophan Synthase: an Emergent Drug Target in the Treatment of Tuberculosis

et al. 2019

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Tryptophan Synthase (TSase) is an emergent therapeutic target in the treatment of tuberculosis. Interest in TSase as a drug target arose from the fact that this enzyme is not present in humans, while in bacteria, like M. tuberculosis, it catalyses the last two steps in the tryptophan biosynthetic pathway. Several inhibitors of TSase have recently been developed, with promising results. However, the exact catalytic mechanism of this enzyme has remained unexplained at the atomic level. The fact that TSase is a multifunctional enzyme, with two dimers, each one with two independent active sites, interconnected by a 25 Å tunnel, has made it a challenging enzyme, from the catalytic point of view. QM/MM calculations were used to analyze and explain the two steps catalyzed by this enzyme. The results provide an atomic‐level clarification of the full catalytic mechanism of this enzyme, offering also important clues for the development of new inhibitors against tuberculosis.

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molUP: A VMD plugin to handle QM and ONIOM calculations using the gaussian software

Cited by 35 publications

References 16 publications

Human Fatty Acid Synthase: A Computational Study of the Transfer of the Acyl Moieties from MAT to the ACP Domain

Human Fatty Acid Synthase: A Computational Study of the Transfer of the Acyl Moieties from MAT to the ACP Domain

Assessing the validity of DLPNO‐CCSD(T) in the calculation of activation and reaction energies of ubiquitous enzymatic reactions

Solving the Catalytic Mechanism of Tryptophan Synthase: an Emergent Drug Target in the Treatment of Tuberculosis

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