V. Lemaitre

Interaction of amiloride and one of its derivatives with Vpu from HIV-1: a molecular dynamics simulation.

Vpu is an 81‐residue membrane protein, with a single transmembrane segment that is encoded by HIV‐1 and is involved in the enhancement of virion release via formation of an ion channel. Cyclohexamethylene amiloride (Hma) has been shown to inhibit ion channel activity. In the present 12‐ns simulation study a putative binding site of Hma blockers in a pentameric model bundle built of parallel aligned helices of the first 32 residues of Vpu was found near Ser‐23. Hma orientates along the channel axis with its alkyl ring pointing inside the pore, which leads to a blockage of the pore.

Full Length Vpu from HIV-1: Combining Molecular Dynamics Simulations with NMR Spectroscopy

Abstract Based on structures made available by solution NMR, molecular models of the protein Vpu from HIV-1 were built and refined by 6 ns MD simulations in a fully hydrated lipid bilayer. Vpu is an 81 amino acid type I integral membrane protein encoded by the human immunodeficiency virus type-1 (HIV-1) and closely related simian immunodeficiency viruses (SIVs). Its role is to amplify viral release. Upon phosphorylation, the cytoplasmic domain adopts a more compact shape with helices 2 and 3 becoming almost parallel to each other. A loss of helicity for several residues belonging to the helices adjacent to both ends of the loop region containing serines 53 and 57 is observed. A fourth helix, present in one of the NMR-based structures of the cytoplasmic domain and located near the C-terminus, is lost upon phosphorylation.

Bionanotechnology with Membrane Proteins: Mechanics and Electronics

Bionanotechnoloy IRC, Physics Department, University of Oxford, Clarendon Laboratory, Parks Road, Oxford OX1 3PU, Oxfordshire, United Kingdom Phone: +44-1865-272269 E-mail: s.antoranzcontera1@physics.ox.ac.uk 2 Biochemistry Department, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom Molecular and Bio-Science Research Group, NTT Basic Research Laboratories, NTT Corporation, 3-1 MorinosatoWakamiya, Atsugi, Kanagawa 243-0198, Japan

Defining Drug Interactions with the Viral Membrane Protein Vpu from HIV-1

The replication of HIV-1 is strongly enhanced by a small membrane protein called virus protein U (Vpu). Vpu achieves its task by (a) interacting with CD4, the HIV-1 receptor, and (b) by amplifying particle release at the site of the plasma membrane. While the first role is due to interactions of the cytoplasmic site of Vpu with CD4, the second role may be due to ion channel activity caused by the self-assembly of the protein. Recently, a blocker has been proposed which abolishes channel activity. In this chapter, the mechanism of blocking is described using computational methods, including a brief overview of other viral ion channel blockers.