Application of QM/MM and QM methods to investigate histone deacetylase 8

Gleeson, Duangkamol; Gleeson, M. Paul

doi:10.1039/c4md00471j

Cited by 9 publications

(7 citation statements)

References 48 publications

(63 reference statements)

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“…Only atoms within 15 Å of DMM substrate were treated flexibly during the QM/MM calculations, except for those atoms that crossed the QM/MM interface. 45,55 The density functional theory (DFT) M06 functional 56 corresponding to the expected bond breaking/forming process under investigation. Single point QM/MM energy calculations were performed using the 6-311+G(d,p) basis set for H, C, N, O and S atoms and TVZP for Mn (∆Ε SP-HL).…”

Section: Qm/mm Calculationsmentioning

confidence: 99%

Probing the Catalytic Mechanism Involved in the Isocitrate Lyase Superfamily: Hybrid Quantum Mechanical/Molecular Mechanical Calculations on 2,3-Dimethylmalate Lyase

2015

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The isocitrate lyase (ICL) superfamily catalyzes the cleavage of the C(2)-C(3) bond of various α-hydroxy acid substrates. Members of the family are found in bacteria, fungi, and plants and include ICL itself, oxaloacetate hydrolase (OAH), 2-methylisocitrate lyase (MICL), and (2R,3S)-dimethylmalate lyase (DMML) among others. ICL and related targets have been the focus of recent studies to treat bacterial and fungal infections, including tuberculosis. The catalytic process by which this family achieves C(2)-C(3) bond breaking is still not clear. Extensive structural studies have been performed on this family, leading to a number of plausible proposals for the catalytic mechanism. In this paper, we have applied quantum mechanical/molecular mechanical (QM/MM) methods to the most recently reported family member, DMML, to assess whether any of the mechanistic proposals offers a clear energetic advantage over the others. Our results suggest that Arg161 is the general base in the reaction and Cys124 is the general acid, giving rise to a rate-determining barrier of approximately 10 kcal/mol.

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Section: Qm/mm Calculationsmentioning

confidence: 99%

Probing the Catalytic Mechanism Involved in the Isocitrate Lyase Superfamily: Hybrid Quantum Mechanical/Molecular Mechanical Calculations on 2,3-Dimethylmalate Lyase

2015

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“…This structural evidence, in conjunction with steady-state kinetic experiments on Danio Rerio CD1 and CD2, suggested that such vicinal histidines are crucial for catalysis in HDAC6, in analogy with histidines in other widely studied HDACs belonging to the class I ( e.g. , HDAC8, − HDAC2, and HDAC3) . For example, in the case of HDAC8, the vicinal His142 and His143 act as general base and acid, respectively, for the activation (via deprotonation) of the nucleophilic water molecule and for the release (via protonation) of the amine product, ultimately released from the enzyme. , Indeed, the structural similarities among all HDACs suggested that the catalytic mechanism for HDAC6 is analogous to that of other HDACs.…”

Section: Introductionmentioning

confidence: 89%

“…In this context, it is also important to emphasize that HDAC6 is unique in the HDAC family, as it is a heterodimeric structure with two different catalytic domains, namely CD1 and CD2. − Intriguingly, the specific biological relevance of each domain is still not fully understood, − although CD2 has been proposed as the most promising target domain for the development of drugs for several diseases. − , …”

Section: Introductionmentioning

confidence: 99%

“…, HDAC8, − HDAC2, and HDAC3) . For example, in the case of HDAC8, the vicinal His142 and His143 act as general base and acid, respectively, for the activation (via deprotonation) of the nucleophilic water molecule and for the release (via protonation) of the amine product, ultimately released from the enzyme. , Indeed, the structural similarities among all HDACs suggested that the catalytic mechanism for HDAC6 is analogous to that of other HDACs. Importantly, the determination of the X-ray structure of the Tyr745Phe mutated form of CD2 of HDAC6 has captured the acylated Lys located in the proximity of the Zn 2+ , as analogously reported for HDAC8 and more recently for HDAC10 .…”

Section: Introductionmentioning

confidence: 99%

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Insights into the Catalytic Mechanism of Domains CD1 and CD2 in Histone Deacetylase 6 from Quantum Calculations

et al. 2021

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The histone deacetylase 6 enzyme, HDAC6, is a metalloprotein with multiple pathophysiological roles and, as such, is the subject of intense research and drug discovery efforts. Different from the HDAC family, HDAC6 is constituted by a heterodimeric structure with two different catalytic domains, namely CD1 and CD2. Intriguingly, the specific biological relevance of each domain is not fully understood yet. However, a wealth of structural and biochemical data collected on HDAC, and in particular more recently on HDAC6, has revealed that the active sites in both CD1 and CD2 conserve a similar structural architecture. In the present work, we have performed a detailed investigation on the mechanistic aspects of catalysis of HDAC6, comparatively analyzing the enzymatic reaction mechanism in CD1 and CD2. Using density functional theory-based computations, we found that the rate-limiting step of the reaction is the nucleophilic attack of the catalytic water for peptide bond hydrolysis in both domains. Remarkably, the transition state for such a step presents a penta-coordinated metal center. In this regard, we have further validated the crucial contribution to catalysis of Tyr residues (Tyr363 in CD1 and Tyr745 in CD2) for the activation of the substrate, in line with kinetics measures. Importantly, we have quantified the effect on catalysis by the positively charged Lys330 residue in CD1. An analogous contribution is missing in CD2. Our calculations also evidence the contribution of distal residues from the reaction center, such as Gly201/582 and Phe202/583. Taken together, our quantum calculations dissect the catalytic mechanism in HDAC6. These findings may help future experimental studies and drug design efforts for selective HDAC6 targeting.

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“…It is much more challenging to simulate metalloproteins based on the empirical MM techniques, so, higher level theoretical models to investigate of protein–ligand binding, and also reactivity, are needed. Gleeson and Gleeson [194] employed hybrid QM/MM methods to study substrate binding and reactivity at HDAC8, which has a putative pathogenic role in neurological conditions including AD and FRDA. The aim of this study was to develop and validate QM and QM/MM HDAC8 models for predicting new Zn binding moieties, and especially analyzing the interactions between new inhibitors and HDAC proteins that are suboptimally described by traditional molecular mechanic methods.…”

Section: Qm/mm Studymentioning

confidence: 99%

In Silico Studies in Drug Research Against Neurodegenerative Diseases

Makhouri

Ghasemi

2018

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Application of QM/MM and QM methods to investigate histone deacetylase 8

Abstract: Computational chemistry plays an important supporting role in the early stages of drug discovery research.

Cited by 9 publications

References 48 publications

Probing the Catalytic Mechanism Involved in the Isocitrate Lyase Superfamily: Hybrid Quantum Mechanical/Molecular Mechanical Calculations on 2,3-Dimethylmalate Lyase

Probing the Catalytic Mechanism Involved in the Isocitrate Lyase Superfamily: Hybrid Quantum Mechanical/Molecular Mechanical Calculations on 2,3-Dimethylmalate Lyase

Insights into the Catalytic Mechanism of Domains CD1 and CD2 in Histone Deacetylase 6 from Quantum Calculations

In Silico Studies in Drug Research Against Neurodegenerative Diseases

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