Molecular Dynamics Simulations of Antibiotic Ceftaroline at the Allosteric Site of Penicillin-Binding Protein 2a (PBP2a)
Molecular Dynamics Simulations of Antibiotic Ceftaroline at the Allosteric Site of Penicillin-Binding Protein 2a (PBP2a)
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DOI：
10.1002/ijch.202000012
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发表时间：
2020-04-16
影响因子：
3.2
通讯作者：
Essex, Jonathan W.
中科院分区：
文献类型：
--
作者：
Chiang, Ying-Chih;Wong, Mabel T. Y.;Essex, Jonathan W.
耐甲氧西林金黄色葡萄球菌 (MRSA) 通过使用转肽酶青霉素结合蛋白 2a (PBP2a) 进行细胞壁合成来耐受 β-内酰胺类抗生素，而转肽酶青霉素结合蛋白 2a (PBP2a) 不能被 β-内酰胺类抑制。有人提出，PBP2a 的活性位点受到两个环的保护，以减少其与 β-内酰胺结合的可能性。先前的晶体学研究表明，一旦天然底物与 PBP2a 的变构域结合，这个受保护的活性位点就会打开反应。这一开放是为了新的β-内酰胺头孢洛林成功治疗MRSA感染的机制而提出的，即。 e.通过它与变构位点结合，从而打开活性位点以进行抑制。在这项工作中，我们利用分子动力学模拟研究了头孢洛林在这个提议的变构位点的结合。使用主力场 CHARMM36 和 Amber ff14SB 观察到不稳定的结合，并且自由能计算无法确认强的变构效应。我们的研究表明，头孢洛林诱导的变构作用充其量是微弱的。
Methicillin-resistant Staphylococcus aureus (MRSA) tolerates beta-lactam antibiotics by carrying out cell wall synthesis with the transpeptidase Penicillin-binding protein 2a (PBP2a), which cannot be inhibited by beta-lactams. It has been proposed that PBP2a's active site is protected by two loops to reduce the probability of it binding with beta-lactams. Previous crystallographic studies suggested that this protected active site opens for reaction once a native substrate binds at an allosteric domain of PBP2a. This opening was proposed for the new beta-lactam ceftaroline's mechanism in successfully treating MRSA infections, i. e. by it binding to the allosteric site, thereby opening the active site to inhibition. In this work, we investigate the binding of ceftaroline at this proposed allosteric site using molecular dynamics simulations. Unstable binding was observed using the major force fields CHARMM36 and Amber ff14SB, and free energy calculations were unable to confirm a strong allosteric effect. Our study suggests that the allosteric effect induced by ceftaroline is weak at best.