Early stages of misfolding of PAP248-286 at two different pH values: An insight from molecular dynamics simulations
PAP248-286 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...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Computational and Structural Biotechnology Journal |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022003944 |
| _version_ | 1797978192191946752 |
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| author | Nikhil Agrawal Emilio Parisini |
| author_facet | Nikhil Agrawal Emilio Parisini |
| author_sort | Nikhil Agrawal |
| collection | DOAJ |
| description | PAP248-286 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 early stages of 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. |
| first_indexed | 2024-04-11T05:20:08Z |
| format | Article |
| id | doaj.art-f93296a6b5ee4d69b6db3c47c8bf78b0 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:20:08Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-f93296a6b5ee4d69b6db3c47c8bf78b02022-12-24T04:54:14ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-012048924901Early stages of misfolding of PAP248-286 at two different pH values: An insight from molecular dynamics simulationsNikhil Agrawal0Emilio Parisini1Latvian Institute of Organic Synthesis, Aizkraukles 21, LV, Riga 1006, Latvia; College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa; Corresponding authors at: Latvian Institute of Organic Synthesis, Aizkraukles 21, LV, Riga 1006, Latvia.Latvian Institute of Organic Synthesis, Aizkraukles 21, LV, Riga 1006, Latvia; Department of Chemistry “G. Ciamician”, University of Bologna, Bologna, Italy; Corresponding authors at: Latvian Institute of Organic Synthesis, Aizkraukles 21, LV, Riga 1006, Latvia.PAP248-286 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 early stages of 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.http://www.sciencedirect.com/science/article/pii/S2001037022003944HIVPAP248-286MD simulationsamyloid |
| spellingShingle | Nikhil Agrawal Emilio Parisini Early stages of misfolding of PAP248-286 at two different pH values: An insight from molecular dynamics simulations Computational and Structural Biotechnology Journal HIV PAP248-286 MD simulations amyloid |
| title | Early stages of misfolding of PAP248-286 at two different pH values: An insight from molecular dynamics simulations |
| title_full | Early stages of misfolding of PAP248-286 at two different pH values: An insight from molecular dynamics simulations |
| title_fullStr | Early stages of misfolding of PAP248-286 at two different pH values: An insight from molecular dynamics simulations |
| title_full_unstemmed | Early stages of misfolding of PAP248-286 at two different pH values: An insight from molecular dynamics simulations |
| title_short | Early stages of misfolding of PAP248-286 at two different pH values: An insight from molecular dynamics simulations |
| title_sort | early stages of misfolding of pap248 286 at two different ph values an insight from molecular dynamics simulations |
| topic | HIV PAP248-286 MD simulations amyloid |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022003944 |
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