Molecular Insight into the Effect of HIV-TAT Protein on Amyloid-<i>β</i> Peptides

Increased deposition of amyloid-beta (A beta) plaques in the brain is a frequent pathological feature observed in human immunodeficiency virus (HIV)-positive patients. Emerging evidence indicates that HIV regulatory proteins, particularly the transactivator of transcription (TAT) protein, could interact with A beta peptide, accelerating the formation of A beta plaques in the brain and potentially contributing to the onset of Alzheimer's disease in individuals with HIV infection. Nevertheless, the molecular mechanisms underlying these processes remain unclear. In the present study, we have used long all-atom molecular dynamics simulations to probe the direct interactions between the TAT protein and A beta peptide at the molecular level. Sampling over 28.0 mu s, our simulations show that TAT protein induces a shift in the A beta monomer ensemble toward elongated conformations, exposing aggregation-prone regions on the surface and thereby inducing subsequent aggregation. TAT protein also appears to enhance the stability of preformed A beta fibrils, while increasing the beta-sheet content within these fibrils. Our atomistically detailed simulations qualitatively agree with previous in vitro and in vivo studies. Importantly, our simulations identify key interactions between A beta and the TAT protein that drive the A beta aggregation process and stabilize the preformed A beta aggregates, which are particularly challenging to obtain through current experimental techniques.