Mechanical aspects of nitrile hydratase enzymatic activity. Steered molecular dynamics simulations of Pseudonocardia thermophila JCM 3095

Pepłowski, Łukasz; Kubiak, Karina; Nowak, Wiesław

doi:10.1016/j.cplett.2008.10.072

Cited by 38 publications

(22 citation statements)

References 41 publications

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“…3b). It is in a good agreement with our previous LES based calculations with other amides 45 . The results on the successful rate and calculated paths characteristics are presented in find an optimal, in terms of receptor's geometry, egress pathway.…”

Section: Enzyme Nitrile Hydratasesupporting

confidence: 92%

Memetic algorithms for ligand expulsion from protein cavities

Rydzewski

Nowak

2015

The Journal of Chemical Physics

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Ligand diffusion through a protein interior is a fundamental process governing biological signaling and enzymatic catalysis. A complex topology of channels in proteins leads often to difficulties in modeling ligand escape pathways by classical molecular dynamics simulations. In this paper two novel memetic methods for searching the exit paths and cavity space exploration are proposed: Memory Enhanced Random Acceleration (MERA) Molecular Dynamics and Immune Algorithm (IA). In MERA, a pheromone concept is introduced to optimize an expulsion force. In IA, hybrid learning protocols are exploited to predict ligand exit paths. They are tested on three protein channels with increasing complexity: M2 muscarinic GPCR receptor, enzyme nitrile hydratase and heme-protein cytochrome P450cam. In these cases, the memetic methods outperform Simulated Annealing and Random Acceleration Molecular Dynamics. The proposed algorithms are general and appropriate in all problems where an accelerated transport of an object through a network of channels is studied.

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Section: Enzyme Nitrile Hydratasesupporting

confidence: 92%

Memetic algorithms for ligand expulsion from protein cavities

Rydzewski

Nowak

2015

The Journal of Chemical Physics

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“…The potential tunnels are calculated. There are several tunnels inside l ‐NHase (Figure S15 A in the Supporting Information), and we have identified one tunnel that fits well with previous X‐ray data and the SMD simulation from all those calculated tunnels (Figure S15 B) . Although other possible ligand/product transfer routes cannot be ruled out definitively, both X‐ray analysis and previous Locally Enhanced Sampling molecular dynamics (MD) simulations of the related Fe‐NHase indicate that this tunnel plays the major role in the NHase function.…”

Section: Methodssupporting

confidence: 86%

“…Although residues βTyr68 and βTrp72 are conserved in all Co‐type NHase, they might be important for substrate selection and binding . βLeu48 and βPhe51 are located at the substrate access tunnel of l ‐NHase, which may be responsible for the fine‐tuning of the substrate selectivity of NHase …”

Section: Resultsmentioning

confidence: 99%

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Modulation of Nitrile Hydratase Regioselectivity towards Dinitriles by Tailoring the Substrate Binding Pocket Residues

et al. 2017

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The regioselective hydration of dinitriles is one of the most attractive approaches to prepare ω‐cyanocarboxamides or diamides and such regioselectivity is often beyond the capability of chemical catalysts. The use of nitrile hydratase to biotransform dinitriles selectively would be highly desirable. Molecular docking of two aliphatic dinitriles and two aromatic dinitriles into the active site of a nitrile hydratase (NHase) from Rhodococcus rhodochrous J1 allowed the identification of proximal NHase substrate binding pocket residues. Four residues (βLeu48, βPhe51, βTyr68, and βTrp72) were selected for single‐ and double‐point mutations to modulate the NHase regioselectivity towards dinitriles. Several NHase mutants with an altered regioselectivity were obtained, and the best one was Y68T/W72Y. Docking experiments further indicated that the poor binding affinity of aliphatic and aromatic ω‐cyanocarboxamides to the NHase variants resulted in distinct regioselectivity between wild‐type and mutated NHases.

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“…The metal ion (Co 3+ ) at the catalytic centre is deeply buried within the α-subunit at the end of a channel lined with bulky aromatic amino acids that control access of substrates [20]. Navigation of small aliphatic nitriles through the channel of the Co-Nhase of Pseudonocardia thermophila has been simulated through computer modelling [21]. The channel and the active site configuration permit enantioselective hydration of nitriles [22][23][24], but are therefore likely to be highly constrained and limit the types of nitrile compounds that will be converted based on configuration and size [25].…”

Section: Introductionmentioning

confidence: 99%

Substrate Profiling of the Cobalt Nitrile Hydratase from Rhodococcus rhodochrous ATCC BAA 870

et al. 2020

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The aromatic substrate profile of the cobalt nitrile hydratase from Rhodococcus rhodochrous ATCC BAA 870 was evaluated against a wide range of nitrile containing compounds (>60). To determine the substrate limits of this enzyme, compounds ranging in size from small (90 Da) to large (325 Da) were evaluated. Larger compounds included those with a bi-aryl axis, prepared by the Suzuki coupling reaction, Morita–Baylis–Hillman adducts, heteroatom-linked diarylpyridines prepared by Buchwald–Hartwig cross-coupling reactions and imidazo[1,2-a]pyridines prepared by the Groebke–Blackburn–Bienaymé multicomponent reaction. The enzyme active site was moderately accommodating, accepting almost all of the small aromatic nitriles, the diarylpyridines and most of the bi-aryl compounds and Morita–Baylis–Hillman products but not the Groebke–Blackburn–Bienaymé products. Nitrile conversion was influenced by steric hindrance around the cyano group, the presence of electron donating groups (e.g., methoxy) on the aromatic ring, and the overall size of the compound.

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Mechanical aspects of nitrile hydratase enzymatic activity. Steered molecular dynamics simulations of Pseudonocardia thermophila JCM 3095

Cited by 38 publications

References 41 publications

Memetic algorithms for ligand expulsion from protein cavities

Memetic algorithms for ligand expulsion from protein cavities

Modulation of Nitrile Hydratase Regioselectivity towards Dinitriles by Tailoring the Substrate Binding Pocket Residues

Substrate Profiling of the Cobalt Nitrile Hydratase from Rhodococcus rhodochrous ATCC BAA 870

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