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BP: Fachverband Biologische Physik

BP 21: Poster IIIb

BP 21.10: Poster

Wednesday, March 20, 2024, 11:00–14:30, Poster C

Free energy calculations of drug permeation through the bacterial outer membranes — •Vasily Unguryan and Jochen Hub — Saarland university, Saarbrücken, Germany

The development of bacterial resistance to antibiotics requires ongoing efforts to find new drugs. For the class of Gram-negative bacteria, their complex outer membrane represents a first and highly selective barrier on the cell-entering pathway for potential drug molecules. The outer leaflet of the membrane is mainly composed of lipopolysaccharides, whose chemical complexity leads to slow lateral diffusion and tight packing compared to phospholipid membranes, thus imposing poor uptake of many drug candidates.

Molecular dynamics simulations may, in principle, rationalize the low permeability of the outer membrane, for instance, by computing the free energy profile for drug permeation along the membrane permeation pathway. Unfortunately, common umbrella sampling simulations, widely used to compute free energy profiles, converge poorly for complex systems such as outer membrane models. In this project, we combine different enhanced sampling techniques to overcome such challenges, with the aim of deriving both free energy and diffusivity profiles for the permeation of bulky drug-like molecules across the outer membrane.

Keywords: Drug-membrane interactions; Bacterial membrane; Molecular dynamics; Umbrella sampling; Enhanced sampling techniques