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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.
摘要：
更好地理解维持蛋白质结构所涉及的力的一个核心方法是研究蛋白质折叠和热力学性质。折叠过程的效果通常在突变状态下受到干扰。为了探索突变背后的动态特性，分子动力学(MD)模拟已经被广泛执行，尤其是揭示突变背后的药物失效机制。当比较野生型(WT)和突变体(MT)时，随着溶剂化自由能(SFE)的结构变化，和吉布斯自由能(GFE)在MD模拟后计算，测量突变对蛋白质结构的影响。吡嗪酰胺（PZA）是一线药物之一，对潜在的结核分枝杆菌分离株有效，影响2030年全球结核病控制计划。由于pncA和rpsA基因的突变，对这种药物产生了耐药性，分别编码吡嗪酰胺酶（PZase）和核糖体蛋白S1（RpsA）。GFE如何衡量PZase和RpsA稳定性的问题，已在当前审查中得到解决。将MT的GFE和SFE与WT进行了比较，已经发现具有PZA抗性。与MT相比，WT结构获得了更稳定的状态。PZase和RpsA中突变的生理效应可能是由于能量的差异。WT和MT之间的差异，通过GFE图描绘，可能有助于预测突变后的稳定性和PZA抗性。这项研究为更好地管理耐药性提供了有用的信息，控制全球结核病问题。
