PROFESSOR Ulrich Kleinekathoefer
Computational Physics
Jacobs University
Bremen, Germany

Monday, November 2, 2020
9:00 am (CT)
Zoom webinar recording

Abstract

Channels in the outer membrane of Gram-negative bacteria provide essential pathways for the controlled and unidirectional transport of ions, nutrients and metabolites into the cell. At the same time, the outer membrane serves as a physical barrier for the penetration of noxious substances such as antibiotics into the bacteria. In this presentation, the simulation of ion and substrate transport through such bacterial channels will be detailed. As examples, the translocations of the antibiotics fosfomycin, ciprofloxacin and enrofloxacin have been computed using molecular simulation techniques. Moreover, we investigated a variety of substrates and their free energy surfaces along the outer membrane channels OprP and OprO of Pseudomonas aeruginosa using the well advanced metadynamics and umbrella sampling free energy methods. The comparison of the two numerical approaches highlights issues when computing the permeation of substrates of increasing complexity through nanopores. These issues will be briefly discussed. To be able to screen more substrates, we developed a Brownian dynamics approach including explicit atoms and obtained encouraging results. Finally, the transport across bacterial membranes with the help of TonB-dependent transporters will be briefly addressed. References: [1] J. D. Prajapati, C. J. F. Solano, M. Winterhalter and U. Kleinekathöfer, Characterization of Ciprofloxacin Permeation Pathways across the Porin OmpC Using Metadynamics and a String Method, J. Chem. Theory Comput. 13, 4553–4566 (2017). [2] V. K. Golla, E. Sans-Serramitjana, K. R. Pothula, L. Benier, J. A. Bafna, M. Winterhalter and U. Kleinekathöfer, Fosfomycin Permeation through the Outer Membrane Porin OmpF, Biophys. J. 116, 258–269 (2019). [3] V. K. Golla, J. D. Prajapati, M. Joshi and U. Kleinekathöfer, Exploration of Free Energy Surfaces across a Membrane Channel Using Metadynamics and Umbrella Sampling, J. Chem. Theory Comput. 16, 2751– 2765 (2020). [4] J. Wang, J. D. Prajapati, U. Kleinekathöfer and M. Winterhalter, Dynamic Interaction of Fluoroquinolone with Magnesium Ions monitored by Bacterial Outer Membrane Nanopores, Chem. Sci. (in press, DOI: 10.1039/D0SC03486J) (2020). [5] A. J. Glenwright, K. R. Pothula, S. P. Bhamidimarri, D. S. Chorev, A. Baslé, S. J. Firbank, H. Zheng, C. V. Robinson, M. Winterhalter, U. Kleinekathöfer, D. N. Bolam und B. van den Berg, Structural Basis for Nutrient Acquisition by Dominant Members of the Human Gut Microbiota, Nature 541, 407–411 (2017). CV: http://ukleinekat.user.jacobs-university.de/cv-of-ulrich- kleinekathofer/ Lab: http://ukleinekat.user.jacobs-university.de/