Quantum mechanical/molecular mechanical studies of zinc hydrolases

Xu, Dingguo; Cui, Qiang; Guo, Hua

doi:10.1080/0144235x.2014.889378

Cited by 21 publications

(19 citation statements)

References 300 publications

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“…For metalloenzyme applications, recent developments have led to promising parameterizations for several metal ions that include the alkali metals, 57 magnesium, zinc 58 and copper. 59 The DFTB3 method in the current form is most reliable for structural properties, including for fairly complex bi-metallic motifs in several enzymes; 40,41,58,60,61 for energetic properties, the results are less robust as compared to DFT/GGA 62,63 but can often be improved to satisfying accuracy with single point energy calculations at high QM(/MM) level, making DFTB3 a promising low-level approach in dual-level QM/MM free energy simulations, a topic that we will also discuss here.…”

Section: Introductionmentioning

confidence: 99%

QM/MM free energy simulations: recent progress and challenges

Dong

Ito

et al. 2016

Molecular Simulation

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Due to the higher computational cost relative to pure molecular mechanical (MM) simulations, hybrid quantum mechanical/molecular mechanical (QM/MM) free energy simulations particularly require a careful consideration of balancing computational cost and accuracy. Here we review several recent developments in free energy methods most relevant to QM/MM simulations and discuss several topics motivated by these developments using simple but informative examples that involve processes in water. For chemical reactions, we highlight the value of invoking enhanced sampling technique (e.g., replica-exchange) in umbrella sampling calculations and the value of including collective environmental variables (e.g., hydration level) in metadynamics simulations; we also illustrate the sensitivity of string calculations, especially free energy along the path, to various parameters in the computation. Alchemical free energy simulations with a specific thermodynamic cycle are used to probe the effect of including the first solvation shell into the QM region when computing solvation free energies. For cases where high-level QM/MM potential functions are needed, we analyze two different approaches: the QM/MM-MFEP method of Yang and co-workers and perturbative correction to low-level QM/MM free energy results. For the examples analyzed here, both approaches seem productive although care needs to be exercised when analyzing the perturbative corrections.

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Section: Introductionmentioning

confidence: 99%

QM/MM free energy simulations: recent progress and challenges

Dong

Ito

et al. 2016

Molecular Simulation

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105

111

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“…Unfortunately, due to inappropriate orientation of ligand residues to Zn in CPA, we then included it in Figure C separately. However, it is well-known that ACE and CPA have a very close substrate binding pocket . Of course, some differences between LTA4H and other peptidases can also be found, e.g., chloride ion dependent activity of ACE.…”

Section: Resultsmentioning

confidence: 99%

“…For bond breaking and formation occurring in the enzyme active site, a multiscale method like the combined quantum mechanics and molecular mechanics (QM/MM) method ,− has shown its power to tackle these issues. In the present study, the self-consistent-charge density functional tight binding (SCC-DFTB) theory − was employed to describe the electronic structure calculation for atoms in the QM region.…”

Section: Computational Detailsmentioning

confidence: 99%

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QM/MM Molecular Dynamics Investigations of the Substrate Binding of Leucotriene A4 Hydrolase: Implication for the Catalytic Mechanism

2018

J. Phys. Chem. B

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LTA4H is a monozinc bifunctional enzyme which exhibits both aminopeptidase and epoxide hydrolase activities. Its dual functions in anti- and pro-inflammatory roles have attracted wide attention to the inhibitor design. In this work, we tried to construct Michaelis complexes of LTA4H with both a native peptide substrate and LTA4 molecule using combined quantum mechanics and molecular mechanics molecular dynamics simulations. First of all, the zinc ion is coordinated by H295, H299, and E318. For its aminopeptidase activity, similar to conventional peptidases, the fourth ligand to the zinc ion is suggested to be an active site water, which is further hydrogen bonded with a downstream glutamic acid, E296. For the epoxide hydrolase activity, the fourth ligand to the zinc ion is found to be an epoxy oxygen atom. The potential of mean force calculation indicates about an 8.5 kcal/mol activation barrier height for the ring-opening reaction, which will generate a metastable carbenium intermediate. Subsequent frontier molecular orbital analyses suggest that the next step would be the nucleophilic attacking reaction at the C12 atom by a water molecule activated by D375. Our simulations also analyzed functions of several important residues like R563, K565, E271, Y383, and Y378 in the binding of peptide and LTA4.

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“…Long-range electrostatics were treated with the Particle-Mesh Ewald algorithm and distance constraints between all H-bonds was enforced by the LINCS algorithm [ 63 ]. Although the employed force field does not appropriately represent the interactions between the catalytic zinc metal ion and the coordinated residues [ 64 ], this metal ion is not considered to have a structural role [ 65 ]. An additional non-biologically relevant zinc ion found at the active site of the crystallographic structure was removed.…”

Section: Methodsmentioning

confidence: 99%

Comparison of the Internal Dynamics of Metalloproteases Provides New Insights on Their Function and Evolution

et al. 2015

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Metalloproteases have evolved in a vast number of biological systems, being one of the most diverse types of proteases and presenting a wide range of folds and catalytic metal ions. Given the increasing understanding of protein internal dynamics and its role in enzyme function, we are interested in assessing how the structural heterogeneity of metalloproteases translates into their dynamics. Therefore, the dynamical profile of the clan MA type protein thermolysin, derived from an Elastic Network Model of protein structure, was evaluated against those obtained from a set of experimental structures and molecular dynamics simulation trajectories. A close correspondence was obtained between modes derived from the coarse-grained model and the subspace of functionally-relevant motions observed experimentally, the later being shown to be encoded in the internal dynamics of the protein. This prompted the use of dynamics-based comparison methods that employ such coarse-grained models in a representative set of clan members, allowing for its quantitative description in terms of structural and dynamical variability. Although members show structural similarity, they nonetheless present distinct dynamical profiles, with no apparent correlation between structural and dynamical relatedness. However, previously unnoticed dynamical similarity was found between the relevant members Carboxypeptidase Pfu, Leishmanolysin, and Botulinum Neurotoxin Type A, despite sharing no structural similarity. Inspection of the respective alignments shows that dynamical similarity has a functional basis, namely the need for maintaining proper intermolecular interactions with the respective substrates. These results suggest that distinct selective pressure mechanisms act on metalloproteases at structural and dynamical levels through the course of their evolution. This work shows how new insights on metalloprotease function and evolution can be assessed with comparison schemes that incorporate information on protein dynamics. The integration of these newly developed tools, if applied to other protein families, can lead to more accurate and descriptive protein classification systems.

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Quantum mechanical/molecular mechanical studies of zinc hydrolases

Cited by 21 publications

References 300 publications

QM/MM free energy simulations: recent progress and challenges

QM/MM free energy simulations: recent progress and challenges

QM/MM Molecular Dynamics Investigations of the Substrate Binding of Leucotriene A4 Hydrolase: Implication for the Catalytic Mechanism

Comparison of the Internal Dynamics of Metalloproteases Provides New Insights on Their Function and Evolution

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