Methodology for the Simulation of Molecular Motors at Different Scales

Singharoy, Abhishek; Chipot, Christophe

doi:10.1021/acs.jpcb.6b09350

Cited by 23 publications

(22 citation statements)

References 116 publications

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“…On the other hand, when the dihedral takes negative values ($20% of the time), the N6 hydrogen bond points inside the active site, allowing interaction with the key residue Ser130 and, in this way, favors the deprotonation of the N6 atom via the proton shuttle toward Lys73 through Ser130. For some molecules, such as proteins, there could be many minima on the energy surface as a result of conformational transitions (31), and the global minimal energy conformation may not be the active conformation. Moreover, the minimal energy states could be separated by high potential barriers.…”

Section: Resultsmentioning

confidence: 99%

Molecular Insights on the Release of Avibactam from the Acyl-Enzyme Complex

Lizana

Delgado

2019

Biophysical Journal

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Avibactam is a non-b-lactam b-lactamase inhibitor for treating complicated urinary tract and respiratory infections caused by multidrug-resistant bacterial pathogens, a serious public health threat. Despite its importance, the release mechanism of avibactam from the enzyme-inhibitor complex has been scarcely studied from first principles, considering the total protein environment. This information at the molecular level is essential for the rational design of new antibiotics and inhibitors. In this article, we addressed the release of avibactam from the complex CTX-M-15 by means of molecular dynamics simulations and quantum mechanics/molecular mechanics calculations. This study provides molecular information not available earlier, including exploration of the potential energy surfaces, characterization of the observed intermediate, and their critical points, as well. Our results show that unlike that observed in the acylation reaction, the residues Glu166 and Lys73 would be in their neutral forms. Release of avibactam follows a stepwise mechanism in which the first stage corresponds to the formation of a tetrahedral intermediate, whereas the second stage corresponds to the cleavage of the Ser70-C7 bond, mediated by Lys73, either directly or through Ser130.

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Section: Resultsmentioning

confidence: 99%

Molecular Insights on the Release of Avibactam from the Acyl-Enzyme Complex

Lizana

Delgado

2019

Biophysical Journal

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“…Qualitative examination of the simulations performed employing the string method with swarms of trajectories of the entire V 1 (Singharoy and Chipot, 2017; Singharoy et al, 2017) did not reveal any significant difference in the conformation of the motor structures determined by crystallography (Arai et al, 2013). Analysis of the sequence of events characterizing the conformational transition in V 1 , however, unveiled additional, subtle, albeit key milestones, absent in the structural studies.…”

Section: Conformational Rotation Pathway Of Ehv1mentioning

confidence: 96%

“…The mechanical changes within a chemically charged V 1 following the hydrolysis step is probed using string simulations with swarms of trajectories (Pan et al, 2008). Combination of the FEP and the string methodologies offers a general theoretical framework for capturing a nanoscale motor in action (Singharoy and Chipot, 2017; Benson et al, 2018). Energy changes along the most probable conformational transition pathway in V 1 , underlying the rotation of the central shaft as a mechanical response to ATP hydrolysis, product (ADP.Pi) release, and binding of a new reactant ATP was found to be approximately 6 kcal/mol (Singharoy et al, 2017).…”

Section: Free-energy Calculations Of Ehv1mentioning

confidence: 99%

“…Finally, a bound ATP (b) in the third site, in A C B O′ form, transitions to the reaction mode in the ‘tight’ (t) conformation, promoting subsequent hydrolysis (4→5). Rates of each of these transitions are computed employing techniques described in Singharoy and Chipot (2017) and Singharoy et al (2017) and labeled along with each step. The rotation step is found to be the slowest when it follows product release.…”

Section: Conformational Rotation Pathway Of Ehv1mentioning

confidence: 99%

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Rotational Mechanism Model of the Bacterial V1 Motor Based on Structural and Computational Analyses

et al. 2019

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V1-ATPase exemplifies the ubiquitous rotary motor, in which a central shaft DF complex rotates inside a hexagonally arranged catalytic A3B3 complex, powered by the energy from ATP hydrolysis. We have recently reported a number of crystal structures of the Enterococcus hirae A3B3DF (V1) complex corresponding to its nucleotide-bound intermediate states, namely the forms waiting for ATP hydrolysis (denoted as catalytic dwell), ATP binding (ATP-binding dwell), and ADP release (ADP-release dwell) along the rotatory catalytic cycle of ATPase. Furthermore, we have performed microsecond-scale molecular dynamics simulations and free-energy calculations to investigate the conformational transitions between these intermediate states and to probe the long-time dynamics of the molecular motor. In this article, the molecular structure and dynamics of the V1-ATPase are reviewed to bring forth a unified model of the motor’s remarkable rotational mechanism.

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“…Cavitands and their inclusion complexes (cavitands with the molecules included in them) in addition to being of academic interest, have practical significance as drug-and fragrance-delivery agents, [1][2][3][4] chemical sensors [5] and food additives [6] . Research involving the inclusion aspect of macrocyclic cavitands have been pursued on several fronts including catalysis, [7][8][9][10][11][12][13][14][15] sensor design, [16,17] molecular architecture, [18,19] chemical syntheses, [20][21][22] materials research, [23,24] and as model systems in supramolecular chemistry. [25][26][27][28] Such applications pivot on cavitands' ability to include and modify physicochemical behavior of guest molecules.…”

Section: Introductionmentioning

confidence: 99%

Cucurbiturils as Reaction Containers for Photocycloaddition of Olefins

Pattabiraman

Sivaguru

Ramamurthy

2017

Israel Journal of Chemistry

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The [2+2] photocycloaddition (PCA [2+2]) of alkenes is one of the most synthetically useful photoreactions. It is a convenient one‐step reaction that is useful for generating substituted cyclobutanes, polymers, and biologically relevant molecules. However, the reaction efficiency is limited by its bimolecular nature requiring encounter between two reactants within the narrow window of excited state lifetime of the photoactive alkene, and competition from the unimolecular photoisomerization. Our groups have utilized macrocyclic cavitands, especially cucurbiturils(CB), to confine two alkene molecules within their cavities and steer them towards a single dimer regio‐ and stereoselectively. Although, primarily the review focuses on photocycloaddition within CBs, such reactions in closely related cavitands such as cyclodextrins (CD) and calixarenes (CA) are also briefly mentioned to provide a comparison with CBs. Studies on photocycloaddition of olefins within CB by other research groups are also briefly highlighted. A mechanistic model, with ability to predict the nature of the dimer product formed within the above reaction containers is included.

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Methodology for the Simulation of Molecular Motors at Different Scales

Cited by 23 publications

References 116 publications

Molecular Insights on the Release of Avibactam from the Acyl-Enzyme Complex

Molecular Insights on the Release of Avibactam from the Acyl-Enzyme Complex

Rotational Mechanism Model of the Bacterial V1 Motor Based on Structural and Computational Analyses

Cucurbiturils as Reaction Containers for Photocycloaddition of Olefins

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