Irregular structure of the HIV fusion peptide in membranes demonstrated by solid-state NMR and MD simulations
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- Grasnick, D., Sternberg, U., Strandberg, E. et al. Eur Biophys J (2011) 40: 529. doi:10.1007/s00249-011-0676-5
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To better understand peptide-induced membrane fusion at a molecular level, we set out to determine the structure of the fusogenic peptide FP23 from the HIV-1 protein gp41 when bound to a lipid bilayer. An established solid-state 19F nuclear magnetic resonance (NMR) approach was used to collect local orientational constraints from a series of CF3-phenylglycine-labeled peptide analogues in macroscopically aligned membranes. Fusion assays showed that these 19F-labels did not significantly affect peptide function. The NMR spectra were characteristic of well-behaved samples, without any signs of heterogeneity or peptide aggregation at 1:300 in 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC). We can conclude from these NMR data that FP23 has a well-defined (time-averaged) conformation and undergoes lateral diffusion in the bilayer plane, presumably as a monomer or small oligomer. Attempts to evaluate its conformation in terms of various secondary structures, however, showed that FP23 does not form any type of regular helix or β-strand. Therefore, all-atom molecular dynamics (MD) simulations were carried out using the orientational NMR constraints as pseudo-forces to drive the peptide into a stable alignment and structure. The resulting picture suggests that FP23 can adopt multiple β-turns and insert obliquely into the membrane. Such irregular conformation explains why the structure of the fusion peptide could not be reliably determined by any biophysical method so far.