Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance.

Muhammad Tahir Khan,Muhammad Tariq Zeb,Dong-Qing Wei,Aman Chandra Kaushik,Sajid Ali,Shaukat Iqbal Malik

doi:10.3389/fmolb.2020.00052

Abstract

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.

Highlights

Evolution may have optimized proteins to perform proper functions, native to the host organism, in different environmental conditions
Understanding the forces like thermodynamic properties and protein folding involved in maintaining the protein structures, is of central interest when working on drug resistance
In the current analysis Gibbs free energy (GFE) along with solvation free energy (SFE) and SE of wild type (WT) and MTs exhibited a significant difference which might be useful in predicting the drug resistance level behind mutations in PZase and RpsA

Summary

Introduction

Evolution may have optimized proteins to perform proper functions, native to the host organism, in different environmental conditions. Pharmaceutical industries desire changes in the thermodynamic properties of a protein (Liszka et al, 2012; Gapsys et al, 2016) to enhance the thermal stability, improving the protein–protein interactions. GRAPHICAL ABSTRACT | Most of the functions are performed by DNA, RNA, and proteins molecules Mutations in these molecules may affect the dynamic properties and free energies, results in weak or loss of interactions. MD simulation studies of ligand-protein interactions are a widely applied approach for explaining the mechanisms of drug resistance behind mutations (Aggarwal et al, 2017; Carter Childers and Daggett, 2017; Bera et al, 2018; Liu et al, 2018; Pandey et al, 2018; Ishima et al, 2019). The dynamics and residues level analysis could be performed which was difficult to achieve through experimental approaches (Hou et al, 2008; Xue et al, 2012; Ding et al, 2013; Khan et al, 2018)

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