Computational analysis of mutations in the transmembrane region of Vpu from HIV-1

AbstractVpu is an 81 amino acid integral membrane protein encoded by HIV-1. Its α-helical transmembrane (TM) domain (residues ∼6–28) enhances virion release by oligomerizing into bundles and forming ion-conducting channels across the plasma membrane. Its cytoplasmic domain (residues ∼29–81) is also α-helical and binds to the transmembrane protein CD4, inducing its degradation. Mutations within the TM domain have been found to abrogate enhanced particle release from the infected cell (Tiganos et al. Virology (1998) 251 96–107). A series of computational models of monomeric, pentameric and hexameric Vpu1–31 mutants have been constructed, embedded in fully hydrated lipid bilayers and subjected to a 3 ns molecular dynamics (MD) simulation. None of the mutations has any destabilizing effect on the secondary and tertiary structure. One of the mutants, in which the position of a tryptophan residue within the TM domain is altered, is known not to induce CD4 degradation; an extended kinked model of this mutant has been generated (Vpu1–52IVW-k) and during subsequent MD simulations, the bend between the TM and a part of the cytoplasmic domain is found to unwind and a complex salt bridge involving Lys-37 is formed