Abstract
T-20 and T-1249 fusion inhibitor peptides were shown to interact with 1-palmitoyl-2-oleyl-phosphatidylcholine (POPC) (liquid disordered, ld) and POPC/cholesterol (1:1) (POPC/Chol) (liquid ordered, lo) bilayers, and they do so to different extents. Although they both possess a tryptophan-rich domain (TRD), T-20 lacks a pocket binding domain (PBD), which is present in T-1249. It has been postulated that the PBD domain enhances FI interaction with HIV gp41 protein and with model membranes. Interaction of these fusion inhibitor peptides with both the cell membrane and the viral envelope membrane is important for function, i.e., inhibition of the fusion process. We address this problem with a molecular dynamics approach focusing on lipid properties, trying to ascertain the consequences and the differences in the interaction of T-20 and T-1249 with ld and lo model membranes. T-20 and T-1249 interactions with model membranes are shown to have measurable and different effects on bilayer structural and dynamical parameters. T-1249’s adsorption to the membrane surface has generally a stronger influence in the measured parameters. The presence of both binding domains in T-1249 appears to be paramount to its stronger interaction, and is shown to have a definite importance in membrane properties upon peptide adsorption.
Highlights
Peptide fusion inhibitors (FI), such as T-20 [1] or T-1249 [2]interfere with human immunodeficiency virus (HIV) fusion of the virus envelope with the immune system cell, effectively inhibiting the process by binding to the protein machinery responsible by recognition and fusion, namely to the gp41 protein [3,4,5,6], the protein responsible for the viral pore formation and membrane fusion [7,8,9]
ApPOPC is the cross-sectional area per POPC molecule, ApCHOL is the cross-sectional area per Chol molecule, Abox is the area of the xy plane of the simulation box, Vbox is the simulation box total volume, Nw is the number of water molecules, Vw is the volume of the water molecule, x = 0.00 or 0.50 is the Chol mole fraction, Nlipid is the number of lipid molecules, VChol is the volume of the Chol molecule [22] and Vpeptide is the volume of the peptide molecule, determined from the peptide simulation in water by averaging Vpeptide = Vbox − Nw × Vw for the last 25 ns of the simulation
Bilayers in two different phases were subject to interaction with two peptide HIV fusion inhibitors: T-20, known as Enfuvirtide, or Fuzeon, already approved and in use in AIDS therapeutics [11], and T-1249, a second generation peptide known to be more effective than the former [9,11,12,15]
Summary
Peptide fusion inhibitors (FI), such as T-20 ( known as Enfuvirtide or Fuzeon) [1] or T-1249 [2]. Concentration of the fusion inhibitors and, improves their availability, maximizing their effectiveness [17] Peptides like these should be able to interact with Chol-rich bilayers, such as the ones of the viral envelope [19,20,21]. A molecular dynamics (MD) approach is used here to evaluate the behavior of membranes in the ld (POPC) and lo (POPC/Chol 1:1) phases upon peptide fusion inhibitor interaction To this effect, parameters, such as H bond formation between membrane lipids and water (Sol), lateral diffusion coefficients (Dlat) of the lipids under scrutiny, rotational dynamics of selected molecular axes and overall acyl chain order parameters, are calculated and discussed
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