Biology subjects

Almeida da Silva, P. E.

Publications and source records attributed to Almeida da Silva, P. E..

2 recordsLinked to original sources

bioRxiv2019

All-atom Molecular Dynamics model for mycobacterial plasma membrane

Phosphatidyl-myo-inositol mannosides (PIMs) are an essential component of the cell envelope and the most predominant at the inner membrane (IM) of M. tuberculosis. In this work, we propose an Molecular Dynamics (MD) M. tuberculosis IM model composed of PIM2 lipids. The study was divided in three parts: influence of the temperature in the PIM2 membrane stability, self-assembly abilities of the PIM2 lipid and the behavior when a trans membrane protein is inserted in PIM2 membrane. Our results show that the model is able to reproduce the gel phase observed at 310 K and the transition to a fluid phase at 328.15 K. Also, the spontaneous self-assembly of randomly distributed lipids in a vesicular aggregate was observed. Finally, we observe that the PIM2 membrane is more stable than DPPC membranes when a Tap protein is inserted. Once Tap eflux pump is related to multidrug resistance of M. tuberculosis, this result indicated that the use of the proper lipid model is essential to the proper depiction and modeling of these systems.\n\nGraphical TOC Entry\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC=\"FIGDIR/small/788299v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (37K):\norg.highwire.dtl.DTLVardef@1409b8dorg.highwire.dtl.DTLVardef@a46772org.highwire.dtl.DTLVardef@183ab3eorg.highwire.dtl.DTLVardef@15fadaa_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2018

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

We 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 -helices, {beta}-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.\n\nImportanceAddressing 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.

bioinformatics↗