Theoretical Model for HIV-1 PR That Accounts for Substrate Recognition and Preferential Cleavage of Natural Substrates
| Autor: | Zainab K. Sanusi, Thavendran Govender, Monsurat M. Lawal, Hendrik G. Kruger, Glenn E. M. Maguire, Bahareh Honarparvar |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Protein Conformation Stereochemistry medicine.medical_treatment Human immunodeficiency virus (HIV) Substrate recognition 010402 general chemistry medicine.disease_cause 01 natural sciences Substrate Specificity HIV Protease Acquired immunodeficiency syndrome (AIDS) 0103 physical sciences Materials Chemistry medicine Amino Acid Sequence Physical and Theoretical Chemistry chemistry.chemical_classification Protease 010304 chemical physics virus diseases Hydrogen-Ion Concentration medicine.disease 0104 chemical sciences Surfaces Coatings and Films Enzyme chemistry HIV-1 Thermodynamics Preferential cleavage |
| Zdroj: | The Journal of Physical Chemistry B. 123:6389-6400 |
| ISSN: | 1520-5207 1520-6106 |
| DOI: | 10.1021/acs.jpcb.9b02207 |
| Popis: | The Human Immunodeficiency Virus type 1 (HIV-1) protease is a crucial target for HIV/AIDS treatment, and understanding its catalytic mechanism is the basis on which HIV-1 enzyme inhibitors are developed. Several experimental studies have indicated that HIV-1 protease facilitates the cleavage of the Gag and Gag-Pol polyproteins and it is highly selective with regard to the cleaved amino acid precursors and physical parameters. However, the main theoretical principles of substrate specificity and recognition remain poorly understood theoretically. By means of a one-step concerted transition state modeling, the recognition of natural substrates by HIV-1 PR subtypes (B and C-SA) was studied. This was carried out to compare the activation free energies at varying peptide bond regions (scissile and nonscissile) within the polypeptide sequence using ONIOM calculations. We studied both P3-P3' and P5-P5' natural substrate systems. For P3-P3' substrates, excellent recognition was observed for the MA-CA family but not for the RH-IN substrates. Satisfactory recognition for the latter was only observed for the longer sequence (P5-P5') after the substrate was subjected to an MD run to maximize the interaction between the enzyme and the substrate. These results indicate that both sequence and structure are important for correct scissile bond recognition of these natural substrates. |
| Databáze: | OpenAIRE |
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