Dual-resolution molecular dynamics simulation of antimicrobials in biomembranes

Abstract

Triclocarban and triclosan, two potent antibacterial molecules present in many consumer products, have been subject to growing debate on a number of issues, particularly in relation to their possible role in causing microbial resistance. In this computational study, we present molecular-level insights into the interaction between these antimicrobial agents and hydrated phospholipid bilayers (taken as a simple model for the cell membrane). Simulations are conducted by a novel 'dual-resolution' molecular dynamics approach which combines accuracy with efficiency: the antimicrobials, modelled atomistically, are mixed with simplified (coarse-grain) models of lipids and water. A first set of calculations is run to study the antimicrobials' transfer free energies and orientations as a function of depth inside the membrane. Both molecules are predicted to preferentially accumulate in the lipid headgroup -glycerol region; this finding, which reproduces corresponding experimental data, is also discussed in terms of a general relation between solute partitioning and the intramembrane distribution of pressure. A second set of runs involves membranes incorporated with different molar concentrations of antimicrobial molecules (up to one antimicrobial per two lipids). We study the effects induced on fundamental membrane properties, such as the electron density, lateral pressure and electrical potential profiles. In particular, the analysis of the spontaneous curvature indicates that increasing antimicrobial concentrations promote a 'destabilizing' tendency towards non-bilayer phases, as observed experimentally. The antimicrobials' influence on the self-assembly process is also investigated. The significance of our results in the context of current theories of antimicrobial action is discussed.

Comparative assessment of the ELBA coarse-grained model for water

“…SSD is a model consisting of a Lennard-Jones sphere, a point dipole, and an additional octupolar term aimed at reproducing hydrogen bonding. SSD has been used to study liquid water and ice [80][81][82][83], and as a solvent in various systems [80,[84][85][86][87][88][89]. In Table 7 we collect results obtained from various slightly different parametrisations of the SSD force field reported in the literature; good agreement with the experiment can be noticed in terms of bulk properties.…”

Shedding light on the puzzle of drug-membrane interactions: Experimental techniques and molecular dynamics simulations

“…Bereau and Kremer (2015) showed that MD simulations with coarse-grained models can lead to free energy profiles that are similar to those obtained by allatom simulations [99]. There are also a number of studies that use a dual-resolution model, where the lipid membrane and the water are simulated using a coarse-grain model, and the drugs, such as β-blocker drugs and antibiotics, are simulated using an atomistic model [100,101]. However, in this review, the focus will be on all-atom MD simulations.…”

“…For example, the permeability was correlated with the permeate size [234], reference solvents [234,235], and free energy barriers [100,101]. Furthermore, cellular automata models have been developed for estimating the membrane permeability of drugs [236,237].…”

Free Energy Calculations for the Peripheral Binding of Proteins/Peptides to an Anionic Membrane. 1. Implicit Membrane Models

“…Different from the unitless binding constant K bind (eq 1) calculated from our simulations, experimentally determined partition coefficients are usually reported as K a = [P] mem /[L][P] aq , where [L] is the concentration of the total lipid. To facilitate a comparison between our simulation with experimental data, we follow the simple correction provided by Tzlil et al 43 (30) where N A is Avogadro's number, a L is the average area per lipid of the membrane (70 Å 2 ), and λ is the membrane bilayer thickness (including the surrounding water, typically 86.6 Å). This leads to…”