title: Structural perturbation of a dipalmitoylphosphatidylcholine (DPPC) bilayer by warfarin and its bolaamphiphilic analogue: A molecular dynamics study.
abstract: Compounds with nominally similar biological activity may exhibit differential toxicity due to differences in their interactions with cell membranes. Many pharmaceutical compounds are amphiphilic and can be taken up by phospholipid bilayers, interacting strongly with the lipid-aqueous interface whether or not subsequent permeation through the bilayer is possible. Bolaamphiphilic compounds, which possess two hydrophilic ends and a hydrophobic linker, can likewise undergo spontaneous uptake by bilayers. While membrane-spanning bolaamphiphiles can stabilize membranes, small molecules with this characteristic have the potential to create membrane defects via disruption of bilayer structure and dynamics. When compared to the amphiphilic therapeutic anticoagulant, warfarin, the bolaamphiphilic analogue, brodifacoum, exhibits heightened toxicity that goes beyond superior inhibition of the pharmacological target enzyme. We explore, herein, the consequences of anticoagulant accumulation in a dipalmitoylphosphatidylcholine (DPPC) bilayer. Coarse-grained molecular dynamics simulations reveal that permeation of phospholipid bilayers by brodifacoum causes a disruption of membrane barrier function that is driven by the bolaamphiphilic nature and size of this molecule. We find that brodifacoum partitioning into bilayers causes membrane thinning and permeabilization and promotes lipid flip-flop - phenomena that are suspected to play a role in triggering cell death. These phenomena are either absent or less pronounced in the case of the less toxic, amphiphilic compound, warfarin.
authors: Department of Chemical Engineering, University of Illinois at Chicago, 810 S. Clinton St., Chicago, IL 60607, USA; Department of Medicine, University of Illinois at Chicago, 909 S. Wolcott Ave., Chicago, IL 60612, USA. Electronic address: mayee2@uic.edu.
authors: Manuela Aseye Ayele
authors: MAA
authors: Ayee
authors: Department of Chemical Engineering, University of Illinois at Chicago, 810 S. Clinton St., Chicago, IL 60607, USA. Electronic address: croth6@uic.edu.
authors: Charles William
authors: CW
authors: Roth
authors: Department of Chemical Engineering, University of Illinois at Chicago, 810 S. Clinton St., Chicago, IL 60607, USA; Department of Molecular Biomedical Sciences, North Carolina State University, 1060 William Moore Dr., Raleigh, NC 27607, USA. Electronic address: bsakpa@ncsu.edu.
authors: Belinda Sena
authors: BS
authors: Akpa
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013501:Surface-Active Agents / Q000737:chemistry*; D014859:Warfarin / Q000737:chemistry*
chemical_list: D008051:Lipid Bilayers; D013501:Surface-Active Agents; D015060:1,2-Dipalmitoylphosphatidylcholine; D014859:Warfarin
keywords: Anticoagulant; Bilayer; Bolaamphiphile; Brodifacoum; Defect; Hydroxycoumarin; Permeation; Phospholipid; Toxicity; Warfarin