The active-inactive transition of human thymidylate synthase: Targeted molecular dynamics simulations

A molecular dynamics simulations of the thymidylate synthase denaturation in chaotrope solvents (urea, guanidinium hydrochloride) were performed on 600 ns timescale. It appeared that this dimeric enzyme undergoes partial unfolding asymmetrically. It was shown also that urea is a better denaturant in the MD condition, as compared to guanidinium chloride. The unfolding occurs first at the external helices (AA 88-118) and follows by the AA 188-200 region. The present results correspond to the suggested in the literature activity of thymidylate synthase through a half-the-site mechanism.

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Targeted Molecular Dynamics Simulations of Protein Unfolding

The Journal of Physical Chemistry B ◽

10.1021/jp9943878 ◽

2000 ◽

Vol 104 (18) ◽

pp. 4511-4518 ◽

Cited By ~ 33

Author(s):

Philippe Ferrara ◽

Joannis Apostolakis ◽

Amedeo Caflisch

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Protein Unfolding ◽

Targeted Molecular Dynamics ◽

Dynamics Simulations

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Investigating the Conformational Preferences of Transforming Growth Factor-β Isoforms using Targeted Molecular Dynamics Simulations

Journal of Chemical Theory and Computation ◽

10.1021/ct800483q ◽

2009 ◽

Vol 5 (3) ◽

pp. 482-490 ◽

Cited By ~ 2

Author(s):

Daniel J. Warner ◽

Ian C. Paterson ◽

Richard B. Sessions

Keyword(s):

Molecular Dynamics ◽

Growth Factor ◽

Molecular Dynamics Simulations ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Targeted Molecular Dynamics ◽

Conformational Preferences ◽

Dynamics Simulations

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Targeted Molecular Dynamics Simulations Suggest Direct Ligand Competition as a Plausible Efflux Inhibition Mechanism in the Multidrug Resistance Pump AcrB

10.1101/339242 ◽

2018 ◽

Author(s):

Lande Silva ◽

Pedro Eduardo Almeida da Silva ◽

Karina S. Machado ◽

Nelson Dutra ◽

Terry P. Lybrand

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Efflux Pump ◽

Outer Part ◽

Inhibition Mechanism ◽

Multidrug Efflux ◽

Multidrug Efflux Pump ◽

Targeted Molecular Dynamics ◽

Calculation Results ◽

Dynamics Simulations

AbstractWe report computer simulation results using the Targeted Molecular Dynamics technique to explore possible transport mechanisms in the multidrug efflux pump AcrB for two substrates, ethidium bromide and a tetrahydropyridine derivative. These studies revealed structural elements, including specific α-helices, β-strands and flexible loops that define a physically plausible pathway for substrates to the extracellular environment. These calculation results can be used to plan future biophysical experiments and may suggest interesting drug design possibilities to address drug resistance due to AcrB function.ImportanceAddressing the issue of antimicrobial resistance mediated by efflux, this study presents possible binding sites and structures in the AcrB MDR pump that could be molecular targets for drugs. Targeted molecular dynamics simulations suggested that these sites and structures seem vital for a successful efflux. The AcrB is proposed to be divided into three distinct zones, with loops, sheets and helices mediating the passage of molecules from one zone to another. We also described possible capture sites on the outer part of the protein and access ways to its interior. Finally, we proposed that ligand competition for same pathways could be thought as an efflux inhibitory mechanism, thus assisting to conceive new ways of designing efflux pump inhibitors.

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