Benchmarking of Density Functionals for the Accurate Description of Thiol–Disulfide Exchange

Neves, Rui P. P.; Fernandes, Pedro A.; Varandas, A. J. C.; Ramos, María J.

doi:10.1021/ct500840f

Cited by 35 publications

(56 citation statements)

References 165 publications

(277 reference statements)

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“…On inclusion of a considerable number of water molecules nearby GSSG at the DFT level (Dataset S5), we determined a TS with a barrier of ∼17 kcal·mol −1 . These results show that, as observed in previous studies (110), the solvent plays a major role in the nucleophilic attack of Cys53 to GSSG (43,45). A detailed discussion is provided in SI Appendix.…”

Section: Resultssupporting

confidence: 86%

“…Several works have shown that the 6-31G(d) basis is adequate for the purpose (85). Furthermore, a previous study has shown that mPW1N (96)(97)(98)(99)(100)(101) [along with mPW1K (96-100, 102, 103), BB1K (104)(105)(106), and mPWB1K (96-100, 104, 107, 108)] is one of the best density functionals to adequately describe the thermochemistry and kinetics of thiol-disulfide exchange (45).…”

Section: Methodsmentioning

confidence: 99%

“…From these aspects, the effect of the hydrogen bond donors in the Cys-X-Y-Cys motif seems to find greater acceptance in academia (39)(40)(41)(42). Earlier theoretical studies using cluster models (43)(44)(45) suggested that thiol-disulfide exchange is an S N 2 reaction, in which a nucleophilic thiolate (S nuc ) linearly attacked a disulfide with concomitant dissociation of the latter. In this reaction, the S nuc and the leaving sulfur (S lg ) are approximately parallel to each other and orthogonal to the central sulfur (S ox ), in such a way that the reactant and product disulfides exhibit a torsion of ∼90°around the S-S bond axis (37,(46)(47)(48).…”

Section: Gsh/gssg Buffer In Catalysis By Hpdimentioning

confidence: 99%

“…Together with the fewer number of hydrogen bond donors for the Cys56-thiolate in the reactant state (GSH red -Cys53···Cys56), it may be responsible for the lower Gibbs activation energy that was registered for the step. In fact, because the trisulfide configuration is a minimum energy in vacuum (43,45), we expected that the Gibbs energy for this reaction depended on the relative stabilization by the environment of the leaving nucleophilic thiolates. TS redox2 was characterized with one imaginary frequency in the DFT layer (111i cm −1 ).…”

Section: −1mentioning

confidence: 99%

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Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase

Neves

Fernandes

Ramos

2017

Proc. Natl. Acad. Sci. U.S.A.

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We explore the enzymatic mechanism of the reduction of glutathione disulfide (GSSG) by the reduced a domain of human protein disulfide isomerase (hPDI) with atomistic resolution. We use classical molecular dynamics and hybrid quantum mechanics/molecular mechanics calculations at the mPW1N/6-311+G(2d,2p):FF99SB//mPW1N/6-31G(d): FF99SB level. The reaction proceeds in two stages: (i) a thiol-disulfide exchange through nucleophilic attack of the Cys53-thiolate to the GSSG-disulfide followed by the deprotonation of Cys56-thiol by Glu47-carboxylate and (ii) a second thiol-disulfide exchange between the Cys56-thiolate and the mixed disulfide intermediate formed in the first step. The Gibbs activation energy for the first stage was 18.7 kcal·mol, and for the second stage, it was 7.2 kcal·mol ). Our results also suggest that the catalysis by protein disulfide isomerase (PDI) and thiol-disulfide exchange is mostly enthalpy-driven (entropy changes below 2 kcal·mol −1 at all stages of the reaction). Hydrogen bonds formed between the backbone of His55 and Cys56 and the Cys56-thiol result in an increase in the Gibbs energy barrier of the first thiol-disulfide exchange. The solvent plays a key role in stabilizing the leaving glutathione thiolate formed. This role is not exclusively electrostatic, because an explicit inclusion of several water molecules at the density-functional theory level is a requisite to form the mixed disulfide intermediate. In the intramolecular oxidation of PDI, a transition state is only observed if hydrogen bond donors are nearby the mixed disulfide intermediate, which emphasizes that the thermochemistry of thiol-disulfide exchange in PDI is influenced by the presence of hydrogen bond donors.PDI | GSH/GSSG buffer | thiol-disulfide exchange | protein folding | ONIOM

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Section: Resultssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Gsh/gssg Buffer In Catalysis By Hpdimentioning

confidence: 99%

Section: −1mentioning

confidence: 99%

See 2 more Smart Citations

Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase

Neves

Fernandes

Ramos

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, such superior performance is still statistical, and easily fails when applied to a single specific system/property. Thus, in the last years, benchmarking studies have been very important to define the best performing methods to study particular chemical systems and properties …”

Section: Introductionmentioning

confidence: 99%

Benchmarking of density functionals for the kinetics and thermodynamics of the hydrolysis of glycosidic bonds catalyzed by glycosidases

Pereira

Ribeiro

Fernandes

et al. 2017

Int J of Quantum Chemistry

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In recent years, there has been an increased interest in understanding the enzymatic mechanism of glycosidases resorting mostly to DFT and DFT/MM calculations. However, the performance of density functionals (DFs) is well known to be system and property dependent. Trends drawn from general studies, despite important to evaluate the quality of the DFs and to pave the way for the development of new DFs, may be misleading when applied to a single specific system/property. To overcome this issue, we carried out a benchmarking study of 40 DFs applied to the geometry optimization and to the electronic barrier height (EBarrier) and electronic energy of reaction (ER) of prototypical glycosidase‐catalyzed reactions. Additionally, we report calculations with SCC‐DFTB and four semiempirical MO methods applied to the same problem. We have used a universal molecular model for retaining glycosidases, comprising only a 22‐atoms system that mimics the active site and substrate. High accuracy reference geometries and energies were calculated at the CCSD(T)/CBS//MP2/aug‐cc‐pVTZ level of theory. Most DFs reproduce the reference geometries extremely well, with mean unsigned errors (MUE) smaller than 0.05 Å for bond lengths and 3° for bond angles. Among the DFs, wB97X‐D, CAM‐B3LYP, B3P86, and PBE1PBE have the best performance in geometry optimizations (MUE = 0.02 Å). Conversely, semiempirical MO and SCC‐DFTB methods yielded less accurate geometries (MUE between 0.09 and 0.17 Å). The inclusion of D3 correction has a small, but still relevant, influence in the geometry predicted by some DFs. Regarding EBarrier, 11 DFs (MPW1B95, CAM‐B3LYP, M06 ‐ 2X, PBE1PBE, wB97X ‐ D, B1B95, BMK, MN12 – SX, M05, M06, and M11) presented errors below 1 kcal.mol−1, in relation to the reference energy. Most of these functionals belong to the family of hybrid functionals (H‐GGA, HH‐GGA, and HM‐GGA), which shows a positive influence of HF exchange in the determination of EBarrier. The inclusion of D3 correction has not affected significantly the EBarrier and ER. The use of geometries at the accurate but expensive MP2/aug‐cc‐pVTZ level of theory has a small, albeit not insignificant, influence in the EBarrier when compared with energies calculated with geometries determined with the DFs (usually a few tenths of kcal.mol−1, with exceptions). In general, semiempirical MO methods and DFTB are associated with larger errors in the determination of EBarrier, with unsigned errors from 6.9 to 24.7 kcal.mol−1.

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Silicon‐Free SuFEx Reactions of Sulfonimidoyl Fluorides: Scope, Enantioselectivity, and Mechanism

et al. 2020

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SuFEx reactions, in which an S−F moiety reacts with a silyl‐protected phenol, have been developed as powerful click reactions. In the current paper we open up the potential of SuFEx reactions as enantioselective reactions, analyze the role of Si and outline the mechanism of this reaction. As a result, fast, high‐yielding, “Si‐free” and enantiospecific SuFEx reactions of sulfonimidoyl fluorides have been developed, and their mechanism shown, by both experimental and theoretical methods, to yield chiral products.

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Benchmarking of Density Functionals for the Accurate Description of Thiol–Disulfide Exchange

Cited by 35 publications

References 165 publications

Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase

Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase

Benchmarking of density functionals for the kinetics and thermodynamics of the hydrolysis of glycosidic bonds catalyzed by glycosidases

Silicon‐Free SuFEx Reactions of Sulfonimidoyl Fluorides: Scope, Enantioselectivity, and Mechanism

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