Department of Biochemistry, School of Biological Sciences, CANS, University of Cape Coast, Cape Coast 00233, Ghana.
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Int J Mol Sci. 2019 Mar 15;20(6):1304. doi: 10.3390/ijms20061304.
The mechanism of the antibiotic molecule A22 is yet to be clearly understood. In a previous study, we carried out molecular dynamics simulations of a monomer of the bacterial actin-like MreB in complex with different nucleotides and A22, and suggested that A22 impedes the release of P from the active site of MreB after the hydrolysis of ATP, resulting in filament instability. On the basis of the suggestion that P release occurs on a similar timescale to polymerization and that polymerization can occur in the absence of nucleotides, we sought in this study to investigate a hypothesis that A22 impedes the conformational change in MreB that is required for polymerization through molecular dynamics simulations of the MreB protofilament in the apo, ATP+, and ATP-A22+ states. We suggest that A22 inhibits MreB in part by antagonizing the ATP-induced structural changes required for polymerization. Our data give further insight into the polymerization/depolymerization dynamics of MreB and the mechanism of A22.
抗生素分子 A22 的作用机制尚不清楚。在之前的一项研究中，我们对与不同核苷酸和 A22 复合的细菌肌动蛋白样 MreB 单体进行了分子动力学模拟，并提出 A22 阻碍了 ADP 水解后 P 从 MreB 活性位点的释放，导致丝不稳定。基于 P 释放与聚合发生的时间尺度相似以及聚合可以在没有核苷酸的情况下发生的假设，我们在这项研究中试图通过对 apo、ATP+ 和 ATP-A22+ 状态下的 MreB 原丝进行分子动力学模拟来验证一个假设，即 A22 通过阻碍 MreB 聚合所需的构象变化来抑制 MreB。我们认为，A22 部分通过拮抗聚合所需的 ATP 诱导的结构变化来抑制 MreB。我们的数据进一步深入了解了 MreB 的聚合/解聚动力学和 A22 的作用机制。
