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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Understanding the resistance mechanism of penicillin binding protein 1a mutant against cefotaxime using molecular dynamic simulation
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Understanding the resistance mechanism of penicillin binding protein 1a mutant against cefotaxime using molecular dynamic simulation

机译：用分子动态模拟理解青霉素结合蛋白1A突变体对头孢噻肟的抗性机制

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摘要

Antibiotic resistance is a threatening challenge for global health, as the expansion of resistance to current antibiotics has made serious therapeutic problems. Genome mutations are key evolutionary mechanisms conferring antibiotic resistance in bacterial pathogens. For example, penicillin and cephalosporins resistance is mostly mediated by mutations in penicillin binding proteins to change the affinity of the drug. Accordingly, threonine point mutations were reported to develop antibiotic resistance in various bacterial infections including pneumococcal infections. In this study, conventional molecular dynamics simulations, umbrella sampling simulations and MM/GBSA free energy calculations were applied to figure out how the Threonine to Alanine mutation (T to A) at STMK motif affects the binding of cefotaxime to Penicillin Binding Protein 1a and to reveal the resistance mechanism induced by the T to A mutation. The results obtained from the computational methods demonstrate that the T to A mutation increases the flexibility of the binding pocket and changes its conformation, which leads to increased conformational entropy change (T擲) and attenuates the bonds between the ligand and the receptor. In brief, our findings indicate that both of the alterations of the conformational enthalpy and entropy contribute to the T to A-induced resistance in the binding of cefotaxime into penicillin binding protein 1a. ?2018, ?2018 Informa UK Limited, trading as Taylor & Francis Group.
机译：抗生素抗性是全球健康的威胁挑战，因为对目前抗生素的抗性扩张已经进行了严重的治疗问题。基因组突变是赋予细菌病原体抗生素抗性的关键进化机制。例如，青霉素和头孢菌素抗性主要由青霉素结合蛋白的突变介导，以改变药物的亲和力。因此，据报道，据报道苏氨酸点突变在各种细菌感染中产生抗生素抗性，包括肺炎球菌感染。在该研究中，常规的分子动力学模拟，伞形采样模拟和MM / GBSA自由能量计算概述了STMK基序的苏氨酸对丙氨酸突变（T至A）的影响会影响头孢噻肟与青霉素结合蛋白1a的结合揭示T突变诱导的抗性机制。从计算方法获得的结果表明，T到突变增加了粘合口的柔韧性并改变其构象，这导致增加构象熵变化（T掷）并衰减配体和受体之间的键。简而言之，我们的研究结果表明，构象焓和熵的两个改变促进了Cefotaxime与青霉素结合蛋白1a的结合中的抗性。 ？2018年，？2018年Informa Informa Limited，贸易为泰勒和弗朗西斯集团。

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