Atomistic detailed mechanism and weak cation-conducting activity of HIV-1 Vpu revealed by free energy calculations.
The viral protein U (Vpu) encoded by HIV-1 has been shown to assist in the detachment of virion particles from infected cells. Vpu forms cation-specific ion channels in host cells, and has been proposed as a potential drug target. An understanding of the mechanism of ion transport through Vpu is desirable, but remains limited because of the unavailability of an experimental structure of the channel. Using a structure of the pentameric form of Vpu--modeled and validated based on available experimental data--umbrella sampling molecular dynamics simulations (cumulative simulation time of more than 0.4 µs) were employed to elucidate the energetics and the molecular mechanism of ion transport in Vpu. Free energy profiles corresponding to the permeation of Na+ and K+ were found to be similar to each other indicating lack of ion selection, consistent with previous experimental studies. The Ser23 residue is shown to enhance ion transport via two mechanisms: creating a weak binding site, and increasing the effective hydrophilic length of the channel, both of which have previously been hypothesized in experiments. A two-dimensional free energy landscape has been computed to model multiple ion permeation, based on which a mechanism for ion conduction is proposed. It is shown that only one ion can pass through the channel at a time. This, along with a stretch of hydrophobic residues in the transmembrane domain of Vpu, explains the slow kinetics of ion conduction. The results are consistent with previous conductance studies that showed Vpu to be a weakly conducting ion channel.
Centre for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad, India.
Siladitya
S
Padhi
Centre for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad, India.
Raghunadha Reddy
RR
Burri
International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
Shahid
S
Jameel
Centre for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad, India.
U Deva
UD
Priyakumar
D015497:HIV-1 / Q000737:chemistry* / Q000378:metabolism; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007473:Ion Channels / Q000737:chemistry* / Q000378:metabolism; D008956:Models, Chemical; D011188:Potassium / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012964:Sodium / Q000737:chemistry* / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins; D000086082:Viroporin Proteins
D054298:Human Immunodeficiency Virus Proteins; D007473:Ion Channels; D011188:Potassium; D012964:Sodium; D054334:Viral Regulatory and Accessory Proteins; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins