Steered Molecular Dynamics Methods Applied to Enzyme Mechanism and Energetics

Ramírez, Claudia Lilián; Martí, Marcelo A.; Roitberg, Adrián E.

doi:10.1016/bs.mie.2016.05.029

Cited by 18 publications

(15 citation statements)

References 36 publications

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“…Molecular dynamics (MD) simulation is a valuable method for calculating the free energy. For example, free energy perturbation, thermodynamics integration, US with the weighted histogram analysis method (WHAM), and steered molecular dynamics (SMD) with US − utilize MD for calculating free energy differences. Sufficient sampling at a reasonable computational cost can be achieved by using enhanced sampling techniques, for example, replica exchange molecular dynamics (REMD), metadynamics, simulated annealing methods, and parallel cascade selection molecular dynamics (PaCS-MD) ,.…”

Section: Introductionmentioning

confidence: 99%

Protein–Ligand Dissociation Simulated by Parallel Cascade Selection Molecular Dynamics

Tran

Takemura

Kuwata

et al. 2017

J. Chem. Theory Comput.

105

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We investigated the dissociation process of tri-N-acetyl-d-glucosamine from hen egg white lysozyme using parallel cascade selection molecular dynamics (PaCS-MD), which comprises cycles of multiple unbiased MD simulations using a selection of MD snapshots as the initial structures for the next cycle. Dissociation was significantly accelerated by PaCS-MD, in which the probability of rare event occurrence toward dissociation was enhanced by the selection and rerandomization of the initial velocities. Although this complex was stable during 1 μs of conventional MD, PaCS-MD easily induced dissociation within 10-10 ns. We found that velocity rerandomization enhances the dissociation of triNAG from the bound state, whereas diffusion plays a more important role in the unbound state. We calculated the dissociation free energy by analyzing all PaCS-MD trajectories using the Markov state model (MSM), compared the results to those obtained by combinations of PaCS-MD and umbrella sampling (US), steered MD (SMD) and US, and SMD and the Jarzynski equality, and experimentally determined binding free energy. PaCS-MD/MSM yielded results most comparable to the experimentally determined binding free energy, independent of simulation parameter variations, and also gave the lowest standard errors.

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Section: Introductionmentioning

confidence: 99%

Protein–Ligand Dissociation Simulated by Parallel Cascade Selection Molecular Dynamics

Tran

Takemura

Kuwata

et al. 2017

J. Chem. Theory Comput.

105

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“…A first guess path for MGL acylation was obtained forcing the progression of the system along the RC by steered-MD (SMD). 43 Analysis of the reaction trajectory shows that acylation occurs through a series of consecutive events: (i) activation of the nucleophile, (ii) nucleophilic attack with generation of a TI, and (iii) protonation of the LG followed by its expulsion, with formation of the acylenzyme. While the SMD simulation provided a feasible reaction pathway for MGL acylation, this method can only coarsely estimate the reaction energetics of a transformation ( Figure S2 ), due to the nonequilibrium conditions applied.…”

Section: Resultsmentioning

confidence: 99%

“…While the SMD simulation provided a feasible reaction pathway for MGL acylation, this method can only coarsely estimate the reaction energetics of a transformation ( Figure S2 ), due to the nonequilibrium conditions applied. 43 We thus extracted a set of geometries along the reaction path covering the space of the RC connecting reactants and products and used them as starting points for US simulations (see Methods for details). 36 This sampling approach, in combination with the weighted histogram analysis method (WHAM), 44 , 45 allowed us to reconstruct the change in free energy due to the progression along the RC, 36 , 38 also known as PMF.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic Modeling of Monoglyceride Lipase Covalent Modification Elucidates the Role of Leaving Group Expulsion and Discriminates Inhibitors with High and Low Potency

Galvani

Scalvini

Rivara

et al. 2022

J. Chem. Inf. Model.

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Inhibition of monoglyceride lipase (MGL), also known as monoacylglycerol lipase (MAGL), has emerged as a promising approach for treating neurological diseases. To gain useful insights in the design of agents with balanced potency and reactivity, we investigated the mechanism of MGL carbamoylation by the reference triazole urea SAR629 (IC 50 = 0.2 nM) and two recently described inhibitors featuring a pyrazole (IC 50 = 1800 nM) or a 4-cyanopyrazole (IC 50 = 8 nM) leaving group (LG), using a hybrid quantum mechanics/molecular mechanics (QM/MM) approach. Opposite to what was found for substrate 2-arachidonoyl- sn -glycerol (2-AG), covalent modification of MGL by azole ureas is controlled by LG expulsion. Simulations indicated that changes in the electronic structure of the LG greatly affect reaction energetics with triazole and 4-cyanopyrazole inhibitors following a more accessible carbamoylation path compared to the unsubstituted pyrazole derivative. The computational protocol provided reaction barriers able to discriminate between MGL inhibitors with different potencies. These results highlight how QM/MM simulations can contribute to elucidating structure–activity relationships and provide insights for the design of covalent inhibitors.

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“…Las enzimas son los catalizadores biológicos por excelencia con alta afinidad de unión específica hacia un sustrato que es inducido al estado de transición, lo estabilizan mediante interacciones entre sus grupos funcionales y además lo orientan para la generación de un producto específico. Las enzimas catalizan una infinidad de reacciones químicas bajo diferentes condiciones en un orden de 10 15 -10 23 veces, y sin ellas los procesos bioquímicos tardarían tanto que la vida no alcanzaría (Ramírez et al, 2016).…”

Section: Importancia De Las Enzimas En Las Reacciones Químicasunclassified

Los retos actuales en la ingeniería de proteínas

Rosales

2019

Cienc. ergo sum

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Las proteínas son la maquinaria molecular que sustenta la vida, y el hombre ha buscado adaptarlas para resolver sus necesidades. En esta revisión, se presentan los fundamentos sobre las proteínas, sus niveles estructurales, plegamiento, las enzimas y su actividad catalítica y las limitantes de sus aplicaciones debido a su naturaleza. De manera simplificada, se ilustran las bases conceptuales y metodológicas de la ingeniería de proteínas, su alcance y las perspectivas de su aplicación en la ciencia y la innovación de procesos. Se concluye que la ingeniería de proteínas es una rama que continúa implementando herramientas computacionales e ingeniería gen´ética-proteómica por medio de la cual es posible la generación de nuevas proteínas para ampliar sus aplicaciones en diversos procesos.

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Steered Molecular Dynamics Methods Applied to Enzyme Mechanism and Energetics

Cited by 18 publications

References 36 publications

Protein–Ligand Dissociation Simulated by Parallel Cascade Selection Molecular Dynamics

Protein–Ligand Dissociation Simulated by Parallel Cascade Selection Molecular Dynamics

Mechanistic Modeling of Monoglyceride Lipase Covalent Modification Elucidates the Role of Leaving Group Expulsion and Discriminates Inhibitors with High and Low Potency

Los retos actuales en la ingeniería de proteínas

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