Dual-resolution molecular dynamics simulation of antimicrobials in biomembranes

• Published in: Journal of the Royal Society interface 2011-06, Vol.8 (59), p.826-841
• Main Authors: Orsi, Mario, Noro, Massimo G., Essex, Jonathan W.
• Format: Article
• Language: English
• Subjects: Anti-Infective Agents - metabolism; Anti-Infective Agents - pharmacology; Antimicrobial agents; Carbanilides; Cell culture; Cell membranes; Computational Biology - methods; Computer applications; Consumers; Data processing; Free energy; Lipids; Membrane Potentials - physiology; Membranes - drug effects; Membranes - metabolism; Models, Biological; Molecular dynamics; Molecular Dynamics Simulation; Molecular modelling; Molecular Structure; Multi-Scale; Phospholipid; Phospholipids; Pressure; Self-Assembly; Solutes; Spontaneous Curvature; Triclocarban; Triclosan
• ISSN: 1742-5689; 1742-5662
• DOI: 10.1098/rsif.2010.0541

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.