Atomistic simulations of PAP248-286 peptide oligomerization
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Atomistic simulations of PAP248-286 peptide oligomerization

A.O. Nikitina*, A.R. Yulmetov**, A.M. Kusova***, V.V. Klochkov****, D.S. Blokhin*****

Kazan Federal University, Kazan, 420008 Russia

E-mail: *annanikitina199737@gmail.com, **ajulmeto@gmail.com, ***alexakusova@mail.ru, ****vklochko@kpfu.ru, *****dblohin@kpfu.ru

Received March 11, 2022

 

ORIGINAL ARTICLE

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DOI: 10.26907/2542-064X.2022.2.185-195

For citation: Nikitina A.O., Yulmetov A.R., Kusova A.M., Klochkov V.V., Blokhin D.S. Atomistic simulations of PAP248-286 peptide oligomerization. Uchenye Zapiski Kazanskogo Universiteta. Seriya Estestvennye Nauki, 2022, vol. 164, no. 2, pp. 185–195. doi: 10.26907/2542-064X.2022.2.185-195.

Abstract

Amyloid fibrils, dubbed SEVI (semen-derived enhancer of virus infection), contribute to the spread of HIV infection. The main components of SEVI are the fragments of prostatic acid phosphatase (PAP): PAP248-286 and PAP85-120. SEVI captures the viral particles and further stimulates their attachment to the target cells, thereby boosting viral fusion and infection. To study the oligomers of SEVI-forming peptides, we used molecular modeling, which is a powerful tool that has been applied in a great variety of studies on SEVI, and an advanced accelerated sampling method of metadynamics. Based on the obtained molecular dynamics data, it was shown that PAP248-286 has a horseshoe shape with bends in the regions of amino acid residues A274 and N269 in the dimeric state. It was suggested that the horseshoe shape might lead in the fibrillation process to the steric zipper model formation, which is typical of amyloids. It was confirmed that the process of fibril formation of PAP248-286 starts with a pairwise parallel arrangement of the peptide helical regions.

Keywords: HIV, prostatic acid phosphatase, SEVI, molecular dynamics, metadynamics

Acknowledgments. This work is supported by the Russian Science Foundation (project no. 20-73-10034). D.S. Blokhin acknowledges the funding from the RF Presidential Council for the State Support of Young Russian Scientists (Candidates of Sciences), project MK-938.2020.4.

Figure Captions

Fig. 1. Percentage of proteins included in aggregation as a function of time.

Fig. 2. Free-energy surface of the PAP248-286 dimerization process as a function of R and NCV.

Fig. 3. The plot of the free energy ΔF vs R for the process of PAP248-286 dimerization.

Fig. 4. Backbone chain RMSD (a) and radius of gyration (b) of the PAP248-286 dimer.

Fig. 5. Structure of the PAP248-286 dimer corresponding to the global minimum of free-energy surface.

Fig. 6. Free-energy surface of PAP248-286: a) trimer, b) tetramer, c) hexamer, and d) heptamer.

Fig. 7. Structure of PAP248-286: a) trimer, b) tetramer, c) hexamer, and d) heptamer. The structures correspond to the global minimum of free-energy surfaces. Key: molecule 1 – red, molecule 2 – orange, molecule 3 – yellow, molecule 4 – green, molecule 5 – cyan, molecule 6 – blue, molecule 7 – magenta.

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