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Structure and Plasticity of the Human Immunodeficiency Virus gp41 Fusion Domain in Lipid Micelles and Bilayers

Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia

Correspondence: Address reprint requests to L. K. Tamm, Tel.: 434-982-3578; E-mail: lkt2e{at}virginia.edu.

A thorough understanding of the structure of fusion domains of enveloped viruses in changing lipid environments helps us to formulate mechanistic models on how they might function in mediating viral entry by membrane fusion. We have expressed the N-terminal fusion domain of HIV-1 gp41 as a construct that is water-soluble in the absence of membranes, but that also binds with high affinity to lipid micelles and bilayers in their presence. We have solved the structure and studied the dynamics of this domain bound to dodecylphosphocholine micelles by homo- and heteronuclear NMR spectroscopy. The fusion peptide forms a stable hydrophobic helix from Ile⁴ to Ala¹⁴, but is increasingly more disordered and dynamic in a segment of intermediate polarity that stretches from Ala¹⁵ to Ser²³. When bound to lipid bilayers at low concentration, the HIV fusion domain is also largely -helical, as determined by CD and FTIR spectroscopy. However, at higher protein/lipid ratios, the domain is partially converted to form ß-structures in lipid bilayers. Controlled lipid mixing occurs at concentrations that support the -helical, but not the ß-strand conformation.

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