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

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.

Mutation-Induced Impacts on the Switch Transformations of the GDP- and GTP-Bound K-Ras: Insights from Multiple Replica Gaussian Accelerated Molecular Dynamics and Free Energy Analysis

“…Although experimental works provide valuable structural bases, they also miss key dynamics information on conformational changes, which is highly significant for drug design. To overcome this shortcoming, a great many computation and simulation technologies, such as conventional molecular dynamics (cMD), − free energy landscapes (FELs), − metadynamics, , essential dynamics (ED) analysis, accelerated molecular dynamics (aMD), , and Gaussian accelerated molecular dynamics (GaMD), − etc., are developed to obtain rational dynamics information concerning conformational alterations of proteins. Furthermore, these technologies have been successfully applied to decode mutation-induced conformational changes and activity adjustment of K-Ras and other Ras proteins. ,− For example, Lu et al performed exchanged nucleotide simulations, and their results unveiled that conformational transformation is more accessible in the GTP-to-GDP exchanges than in the GDP-to-GTP one .…”

Emerging mutations in envelope protein of SARS-CoV-2 and their effect on thermodynamic properties

“…The green areas in P71S, L73F are more prevalent that WT which shows stability next to blue regions. These result demonstrates that E protein MTs might be useful to cause viral pathogenecity [ [60] , [61] , [62] ]. Calculating G might be important to observe the overall stability upon mutations.…”

Uncovering the Mechanism of Drug Resistance Caused by the T790M Mutation in EGFR Kinase From Absolute Binding Free Energy Calculations

“…The binding free energy acts as a useful index to evaluate the binding affinity between mutants and drugs, and can be used as an important indicator of drug resistance ( Zhou et al, 2013 ; Ma et al, 2015 ; Khan et al, 2020 ). In this article, the standard binding free-energy calculations of all systems were performed employing BFEE2 and following a geometrical route ( Gumbart et al, 2013 ; Fu et al, 2021 ; Fu et al, 2022 ).…”