SCL Seminar by Stefan Milenkovic

SCL seminar of the Center for the Study of Complex Systems, will be held on Thursday, 21 December 2017 at 14:00 in the library reading room “Dr. Dragan Popović" of the Institute of Physics Belgrade. The talk entitled

"Exploring PfeA-enterobactin interactions with molecular simulations"

will be given by Dr. Stefan Milenković (Department of Physics, University of Cagliari, Italy).

Abstract of the talk:

Growing antibiotic resistance of bacterial pathogens is one of the key health problems of our days, as pointed out by WHO. A promising strategy for overcoming this issue is a "Trojan-horse" approach, where internal properties of bacteria are used to "smuggle" antibiotics, in this case, through the TonB-dependent transporters. Aiming to find efficient Trojan-horse candidates, we must gather existing and acquire an additional knowledge about binding to and translocation by TonB-dependent transporters. Binding and translocation of the enterobactin molecule (ENT) through the cathecolate transporter PfeA of P. aeruginosa could serve as a test-case for this biological process.

In this talk, we will present a combination of computational techniques such as cavity detection algorithms, molecular docking, molecular dynamics, and enhanced sampling simulations, which are applied to get a detailed molecular description of the PfeA-ENT complex. We will also show a correlation analysis which reveals that the distributions and sizes of the detected cavities are controlled by the collective H-bonding interactions formed between the plug and the rest of the protein. Our findings agree with the experimental results and show how the establishment of the above H-bonds network would represent a unique signal of ENT binding, which is indeed completely absent for the PfeA-apo simulation and appears to be reduced for a double-mutant. Further, with metadynamics simulations we have quantified the residence time of ENT in the binding site. In agreement with experimental data, we found marked differences between the wild-type and double-mutant variants of PfeA, with the latter showing a weak binding. Eventually, by combining metadynamics, cavity analysis and a completely blind docking search, we propose a possible translocation pathway for ENT, from extracellular to periplasmic space, along which free-energy barrier is crucially controlled by plug-barrel H-bond interactions.

[1] R. Annamalai, et al., J. Bacteriol. 186, 3578 (2004).
[2] P. Tiwary and M. Parrinello, Phys. Rev. Lett. 111, 230602 (2013).
[3] M. A. Scorciapino, et al., J. Am. Chem. Soc. 131, 11825 (2009).

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