Author:
Agrawal Nikhil,Parisini Emilio
Abstract
AbstractPAP248-286 peptides, which are highly abundant in human semen, aggregate and form amyloid fibrils that enhance HIV infection. Previous experimental studies have shown that the infection-promoting activity of PAP248-286 begins to increase well before amyloid formation takes place and that pH plays a key role in the enhancement of PAP248-286-related infection. Hence, understanding the early stages of misfolding of the PAP2482-86 peptide is crucial. To this end, we have performed 60 independent MD simulations for a total of 24 μs at two different pH values (4.2 and 7.2). Our data shows that misfolding of the PAP248-286 peptide is a multistage process and that the first step of the process is a transition from an “I-shaped” structure to a “U-shaped” structure. We further observed that the structure of PAP248-286 at the two different pH values shows significantly different features. At pH 4.2, the peptide has less intra-molecular H-bonds and a reduced α-helical content than at pH 7.2. Moreover, differences in intra-peptide residues contacts are also observed at the two pH values. Finally, free energy landscape analysis shows that there are more local minima in the energy surface of the peptide at pH 7.2 than at pH 4.2. Overall, the present study elucidates the early stages of misfolding of the PAP248-286 peptide at the atomic level, thus possibly opening new avenues in structure-based drug discovery against HIV infection.
Publisher
Cold Spring Harbor Laboratory
Reference54 articles.
1. Romero, R. A. ; Klausner, J. D. ; Marsch, L. A. ; Young, S. D. , Technology-Delivered Intervention Strategies to Bolster HIV Testing. Current HIV/AIDS Reports 2021, 1–15.
2. Khalid, K. ; Padda, J. ; Fernando, R. W. ; Mehta, K. A. ; Almanie, A. H. ; Al Hennawi, H. ; Padda, S. ; Cooper, A. C. , Stem Cell Therapy and Its Significance in HIV Infection. Cureus 2021, 13 (8).
3. Role of Semen in HIV-1 Transmission: Inhibitor or facilitator?;American journal of reproductive immunology,2011
4. Detectable HIV-1 in semen in individuals with very low blood viral loads;Virology journal,2020
5. Brief Report: Anal Intercourse, HIV-1 Risk, and Efficacy in a Trial of a Dapivirine Vaginal Ring for HIV-1 Prevention;JAIDS Journal of Acquired Immune Deficiency Syndromes,2020