Unraveling the concerted catalytic mechanism of the human immunodeficiency virus type 1 (HIV-1) protease: a hybrid QM/MM study

Lawal, Monsurat M.; Sanusi, Zainab K.; Govender, Thavendran; Tolufashe, Gideon F.; Maguire, Glenn E. M.; Honarparvar, Bahareh; Kruger, Hendrik G.

doi:10.1007/s11224-018-1251-9

Cited by 16 publications

(34 citation statements)

References 59 publications

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“…Therefore, the development of TYR inhibitors with efficient bioactivity and less toxicity is a relevant branch of scientific research. Recently, we have used molecular modeling approaches to investigate biomolecular systems with an emphasis on enzymatic reactions and inhibition [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluating the Performance of a Non-Bonded Cu2+ Model Including Jahn−Teller Effect into the Binding of Tyrosinase Inhibitors

Martins

Lameira

Kruger

et al. 2020

IJMS

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Tyrosinase (TYR) is a metalloenzyme classified as a type-3 copper protein, which is involved in the synthesis of melanin through a catalytic process beginning with the conversion of the amino acid l-Tyrosine (l-Tyr) to l-3,4-dihydroxyphenylalanine (l-DOPA). It plays an important role in the mechanism of melanogenesis in various organisms including mammals, plants, and fungi. Herein, we used a combination of computational molecular modeling techniques including molecular dynamic (MD) simulations and the linear interaction energy (LIE) model to evaluate the binding free energy of a set of analogs of kojic acid (KA) in complex with TYR. For the MD simulations, we used a dummy model including the description of the Jahn–Teller effect for Cu2+ ions in the active site of this enzyme. Our results show that the LIE model predicts the TYR binding affinities of the inhibitor in close agreement to experimental results. Overall, we demonstrate that the classical model provides a suitable description of the main interactions between analogs of KA and Cu2+ ions in the active site of TYR.

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Section: Introductionmentioning

confidence: 99%

Evaluating the Performance of a Non-Bonded Cu2+ Model Including Jahn−Teller Effect into the Binding of Tyrosinase Inhibitors

Martins

Lameira

Kruger

et al. 2020

IJMS

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“…On the other hand, the reaction Gibbs free energies (∆G R ) were calculated through the difference between the energy of product and reactant for each step. This computational approach has already been successfully employed to study the catalytic mechanism of several enzymes [56][57][58][59][60][61][62], including proteases [63][64][65].…”

Section: Qm/mm Modelmentioning

confidence: 99%

New insights into the catalytic mechanism of the SARS-CoV-2 main protease: an ONIOM QM/MM approach

2021

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SARS-CoV-2 M pro , also known as the main protease or 3C-like protease, is a key enzyme involved in the replication process of the virus that is causing the COVID-19 pandemic. It is also the most promising antiviral drug target targeting SARS-CoV-2 virus. In this work, the catalytic mechanism of M pro was studied using the full model of the enzyme and a computational QM/MM methodology with a 69/72-atoms QM region treated at DLPNO-CCSD(T)/CBS//B3LYP/6-31G(d,p):AMBER level and including the catalytic important oxyanion-hole residues. The transition state of each step was fully characterized and described together with the related reactants and products. The rate-limiting step of the catalytic process is the hydrolysis of the thioester-enzyme adduct, and the calculated barrier closely agrees with the available kinetic data. The calculated Gibbs free energy profile, together with the full atomistic detail of the structures involved in catalysis, can now serve as valuable models for the rational drug design of transition state analogs as new inhibitors targeting the SARS-CoV-2 virus.

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“…In these studies, cyclic TS structures were employed, yielding activation free energies (Δ G ⧧ ) of 30.0 and 43.5 kcal mol –1 . Most recently, the feasibility of the concerted general acid–base model involving two 6-membered TS, with either one or two water molecules, plus an acyclic TS (involving one water molecule) was investigated (Scheme ). The study utilizes MD and the hybrid QM/MM approach in which experimentally comparable results (Δ G ⧧ = 15.2–26.4 kcal mol –1 ) were obtained.…”

Section: Introductionmentioning

confidence: 99%

“…Most recently, the feasibility of the concerted general acid–base model involving two 6-membered TS, with either one or two water molecules, plus an acyclic TS (involving one water molecule) was investigated (Scheme ). The study utilizes MD and the hybrid QM/MM approach in which experimentally comparable results (Δ G ⧧ = 15.2–26.4 kcal mol –1 ) were obtained. From experimental data, Δ G ⧧ between 14.86 and 21.03 kcal mol –1 was estimated depending on the peptide sequence. ,,− …”

Section: Introductionmentioning

confidence: 99%

“…To the best of our knowledge, on the basis of the latest literature review, examining preferential cleavage of the natural substrates of HIV-1 PR via a concerted TS modeling using both MD and QM/MM methods has not been reported elsewhere. The one-step concerted acyclic general acid–base mechanism requires monoprotonation of one aspartate in the active site of the enzyme (Scheme a) . The water molecule and both catalytic Asp (25/25′) are involved in the reaction mechanism, where the acidic Asp (protonated) loses its proton and becomes a base and the unprotonated Asp (base) becomes acidic by gaining a proton.…”

Section: Introductionmentioning

confidence: 99%

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Theoretical Model for HIV-1 PR That Accounts for Substrate Recognition and Preferential Cleavage of Natural Substrates

Sanusi

Lawal

Govender³

et al. 2019

J. Phys. Chem. B

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The Human Immunodeficiency Virus type 1 (HIV-1) protease is a crucial target for HIV/AIDS treatment, and understanding its catalytic mechanism is the basis on which HIV-1 enzyme inhibitors are developed. Several experimental studies have indicated that HIV-1 protease facilitates the cleavage of the Gag and Gag-Pol polyproteins and it is highly selective with regard to the cleaved amino acid precursors and physical parameters. However, the main theoretical principles of substrate specificity and recognition remain poorly understood theoretically. By means of a one-step concerted transition state modeling, the recognition of natural substrates by HIV-1 PR subtypes (B and C-SA) was studied. This was carried out to compare the activation free energies at varying peptide bond regions (scissile and nonscissile) within the polypeptide sequence using ONIOM calculations. We studied both P3–P3′ and P5–P5′ natural substrate systems. For P3–P3′ substrates, excellent recognition was observed for the MA-CA family but not for the RH-IN substrates. Satisfactory recognition for the latter was only observed for the longer sequence (P5–P5′) after the substrate was subjected to an MD run to maximize the interaction between the enzyme and the substrate. These results indicate that both sequence and structure are important for correct scissile bond recognition of these natural substrates.

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Unraveling the concerted catalytic mechanism of the human immunodeficiency virus type 1 (HIV-1) protease: a hybrid QM/MM study

Cited by 16 publications

References 59 publications

Evaluating the Performance of a Non-Bonded Cu2+ Model Including Jahn−Teller Effect into the Binding of Tyrosinase Inhibitors

Evaluating the Performance of a Non-Bonded Cu2+ Model Including Jahn−Teller Effect into the Binding of Tyrosinase Inhibitors

New insights into the catalytic mechanism of the SARS-CoV-2 main protease: an ONIOM QM/MM approach

Theoretical Model for HIV-1 PR That Accounts for Substrate Recognition and Preferential Cleavage of Natural Substrates

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