| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | Costa, Mauricio GS Benetti-Barbosa, Técio G Desdouits, Nathan Blondel, Arnaud Bisch, Paulo M Pascutti, Pedro G Batista, Paulo R |
| Abstract | Background Over the last decades, a vast structural knowledge has been gathered on the HIV-1 protease (PR). Noticeably, most of the studies focused the B-subtype, which has the highest prevalence in developed countries. Accordingly, currently available anti-HIV drugs target this subtype, with considerable benefits for the corresponding patients. However, in developing countries, there is a wide variety of HIV-1 subtypes carrying PR polymorphisms related to reduced drug susceptibility. The non-active site mutation, M36I, is the most frequent polymorphism, and is considered as a non-B subtype marker. Yet, the structural impact of this substitution on the PR structure and on the interaction with natural substrates remains poorly documented. Results Herein, we used molecular dynamics simulations to investigate the role of this polymorphism on the interaction of PR with six of its natural cleavage-sites substrates. Free energy analyses by MMPB/SA calculations showed an affinity decrease of M36I-PR for the majority of its substrates. The only exceptions were the RT-RH, with equivalent affinity, and the RH-IN, for which an increased affinity was found. Furthermore, molecular simulations suggest that, unlike other peptides, RH-IN induced larger structural fluctuations in the wild-type enzyme than in the M36I variant. Conclusions With multiple approaches and analyses we identified structural and dynamical determinants associated with the changes found in the binding affinity of the M36I variant. This mutation influences the flexibility of both PR and its complexed substrate. The observed impact of M36I, suggest that combination with other non-B subtype polymorphisms, could lead to major effects on the interaction with the 12 known cleavage sites, which should impact the virion maturation. |
| Related Links | https://bmcgenomics.biomedcentral.com/counter/pdf/10.1186/1471-2164-15-S7-S5.pdf |
| Ending Page | 15 |
| Page Count | 15 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| ISSN | 14712164 |
| DOI | 10.1186/1471-2164-15-S7-S5 |
| Journal | BMC Genomics |
| Issue Number | 7 |
| Volume Number | 15 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2014-10-27 |
| Access Restriction | Open |
| Subject Keyword | Life Sciences Microarrays Proteomics Animal Genetics and Genomics Microbial Genetics and Genomics Plant Genetics and Genomics Solvation Free Energy Molecular Dynamic Trajectory Root Mean Square Fluctuation Root Mean Square Deviation Free Energy Landscape |
| Content Type | Text |
| Resource Type | Article |
| Subject | Biotechnology Genetics |
| Journal Impact Factor | 3.5/2023 |
| 5-Year Journal Impact Factor | 4.1/2023 |
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