Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance
A central approach for better understanding the forces involved in maintaining protein structures is to investigate the protein folding and thermodynamic properties. The effect of the folding process is often disturbed in mutated states. To explore the dynamic properties behind mutations, molecular...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-04-01
|
| Series: | Frontiers in Molecular Biosciences |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fmolb.2020.00052/full |
| _version_ | 1819162210981642240 |
|---|---|
| author | Muhammad Tahir Khan Sajid Ali Muhammad Tariq Zeb Aman Chandra Kaushik Shaukat Iqbal Malik Dong-Qing Wei Dong-Qing Wei |
| author_facet | Muhammad Tahir Khan Sajid Ali Muhammad Tariq Zeb Aman Chandra Kaushik Shaukat Iqbal Malik Dong-Qing Wei Dong-Qing Wei |
| author_sort | Muhammad Tahir Khan |
| collection | DOAJ |
| description | A central approach for better understanding the forces involved in maintaining protein structures is to investigate the protein folding and thermodynamic properties. The effect of the folding process is often disturbed in mutated states. To explore the dynamic properties behind mutations, molecular dynamic (MD) simulations have been widely performed, especially in unveiling the mechanism of drug failure behind mutation. When comparing wild type (WT) and mutants (MTs), the structural changes along with solvation free energy (SFE), and Gibbs free energy (GFE) are calculated after the MD simulation, to measure the effect of mutations on protein structure. Pyrazinamide (PZA) is one of the first-line drugs, effective against latent Mycobacterium tuberculosis isolates, affecting the global TB control program 2030. Resistance to this drug emerges due to mutations in pncA and rpsA genes, encoding pyrazinamidase (PZase) and ribosomal protein S1 (RpsA) respectively. The question of how the GFE may be a measure of PZase and RpsA stabilities, has been addressed in the current review. The GFE and SFE of MTs have been compared with WT, which were already found to be PZA-resistant. WT structures attained a more stable state in comparison with MTs. The physiological effect of a mutation in PZase and RpsA may be due to the difference in energies. This difference between WT and MTs, depicted through GFE plots, might be useful in predicting the stability and PZA-resistance behind mutation. This study provides useful information for better management of drug resistance, to control the global TB problem. |
| first_indexed | 2024-12-22T17:24:37Z |
| format | Article |
| id | doaj.art-b2668334f0514adfadcce80b4246ff8a |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-22T17:24:37Z |
| publishDate | 2020-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-b2668334f0514adfadcce80b4246ff8a2022-12-21T18:18:45ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2020-04-01710.3389/fmolb.2020.00052507722Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide ResistanceMuhammad Tahir Khan0Sajid Ali1Muhammad Tariq Zeb2Aman Chandra Kaushik3Shaukat Iqbal Malik4Dong-Qing Wei5Dong-Qing Wei6Department of Bioinformatics and Biosciences, Capital University of Science and Technology, Islamabad, PakistanDepartment of Microbiology, Quaid-i-Azam University Islamabad, Islamabad, PakistanVeterinary Research Institute, Peshawar, PakistanState Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, and Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Bioinformatics and Biosciences, Capital University of Science and Technology, Islamabad, PakistanState Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, and Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education, Shanghai Jiao Tong University, Shanghai, ChinaPeng Cheng Laboratory, Shenzhen, ChinaA central approach for better understanding the forces involved in maintaining protein structures is to investigate the protein folding and thermodynamic properties. The effect of the folding process is often disturbed in mutated states. To explore the dynamic properties behind mutations, molecular dynamic (MD) simulations have been widely performed, especially in unveiling the mechanism of drug failure behind mutation. When comparing wild type (WT) and mutants (MTs), the structural changes along with solvation free energy (SFE), and Gibbs free energy (GFE) are calculated after the MD simulation, to measure the effect of mutations on protein structure. Pyrazinamide (PZA) is one of the first-line drugs, effective against latent Mycobacterium tuberculosis isolates, affecting the global TB control program 2030. Resistance to this drug emerges due to mutations in pncA and rpsA genes, encoding pyrazinamidase (PZase) and ribosomal protein S1 (RpsA) respectively. The question of how the GFE may be a measure of PZase and RpsA stabilities, has been addressed in the current review. The GFE and SFE of MTs have been compared with WT, which were already found to be PZA-resistant. WT structures attained a more stable state in comparison with MTs. The physiological effect of a mutation in PZase and RpsA may be due to the difference in energies. This difference between WT and MTs, depicted through GFE plots, might be useful in predicting the stability and PZA-resistance behind mutation. This study provides useful information for better management of drug resistance, to control the global TB problem.https://www.frontiersin.org/article/10.3389/fmolb.2020.00052/fullGFEwild typemutantsPZaseRpsAresistance |
| spellingShingle | Muhammad Tahir Khan Sajid Ali Muhammad Tariq Zeb Aman Chandra Kaushik Shaukat Iqbal Malik Dong-Qing Wei Dong-Qing Wei Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance Frontiers in Molecular Biosciences GFE wild type mutants PZase RpsA resistance |
| title | Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance |
| title_full | Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance |
| title_fullStr | Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance |
| title_full_unstemmed | Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance |
| title_short | Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance |
| title_sort | gibbs free energy calculation of mutation in pnca and rpsa associated with pyrazinamide resistance |
| topic | GFE wild type mutants PZase RpsA resistance |
| url | https://www.frontiersin.org/article/10.3389/fmolb.2020.00052/full |
| work_keys_str_mv | AT muhammadtahirkhan gibbsfreeenergycalculationofmutationinpncaandrpsaassociatedwithpyrazinamideresistance AT sajidali gibbsfreeenergycalculationofmutationinpncaandrpsaassociatedwithpyrazinamideresistance AT muhammadtariqzeb gibbsfreeenergycalculationofmutationinpncaandrpsaassociatedwithpyrazinamideresistance AT amanchandrakaushik gibbsfreeenergycalculationofmutationinpncaandrpsaassociatedwithpyrazinamideresistance AT shaukatiqbalmalik gibbsfreeenergycalculationofmutationinpncaandrpsaassociatedwithpyrazinamideresistance AT dongqingwei gibbsfreeenergycalculationofmutationinpncaandrpsaassociatedwithpyrazinamideresistance AT dongqingwei gibbsfreeenergycalculationofmutationinpncaandrpsaassociatedwithpyrazinamideresistance |