当前位置: X-MOL 学术J. Mol. Graph. Model. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Conformational transition of Acinetobacter baumannii KdsC enzyme and the role of magnesium in binding: An insight from comparative molecular dynamics simulation and its implications in novel antibiotics design.
Journal of Molecular Graphics and Modelling ( IF 2.7 ) Pub Date : 2020-05-07 , DOI: 10.1016/j.jmgm.2020.107625
Tayyaba Gulistan 1 , Sajjad Ahmad 1 , Syed Sikander Azam 1
Affiliation  

The 3-deoxy-d-manno-octulosonate 8-phosphate phosphatase (KdsC) catalyzes the hydrolysis of 3-deoxy-d-manno-octulosonate 8-phosphate (KDO 8-P) to 3-deoxy-d-manno-octulosonate (KDO) and inorganic phosphate in KDO biosynthesis pathway of Gram-negative bacteria lipopolysaccharide (LPS) hydrophobic lipid-A core. The essentiality of KDO for bacterial cell viability presents the possibility of its targeting to develop broad-spectrum antibacterial agents. In this study, a receptor based virtually screening method was put forward to identify novel lead inhibitory molecules for KdsC enzyme. Dynamics evaluation in solution revealed three complexes: Asinex-1197, Asinex-1705, and Asinex-1710 from Asinex antibacterial library as highly stable, involving conformational transition from open to close upon lead molecules binding and eloquent role of active pocket magnesium towards inhibitors binding and movements. Interconversion of local secondary structure elements in sequence region of Asp192-Asp208 covering motif β-turn, β-hairpin, and β-sheets is seen recurrently that could be in all likelihood of the pressure excreted on this region during closing conformation event or magnesium driven inhibitor adjustments. The binding free energy estimation predicted gas phase energy for all the three complexes dominating with major contribution from van der Waals energy (in case of Asinex-1705 and Asinex-1710) and balanced contributions of both electrostatic and van der Waals (in case of Asinex-1197). Key residues-scanning shortlisted Leu45, Asp185, Gy188, Arg231, and Lys255 as vital in the interaction network of magnesium and inhibitors at the binding site. Their crucial roles in net binding energy were reaffirmed via in silico site directed alanine scanning method. The filtered hits might be useful to further scaffolds addition and structural optimization to yield high affinity binders of KdsC enzyme, whose inhibition, in turn, will disrupt the outer membrane synthesis.



中文翻译:

鲍曼不动杆菌KdsC酶的构象转变和镁在结合中的作用:比较分子动力学模拟及其对新型抗生素设计的启示。

3-脱氧d -manno-octulosonate 8磷酸磷酸酶(KdsC)催化3-脱氧的水解d -manno-octulosonate 8磷酸(KDO 8-P)为3-脱氧d革兰氏阴性菌脂多糖(LPS)疏水性脂质A核心的KDO生物合成途径中,β-甘露糖醛酸八甘醇酸酯(KDO)和无机磷酸盐。KDO对于细菌细胞生存力的必要性提出了其靶向开发广谱抗菌剂的可能性。在这项研究中,提出了一种基于受体的虚拟筛选方法来鉴定KdsC酶的新型铅抑制分子。溶液中的动力学评估揭示了三种复合物:来自Asinex抗菌文库的Asinex-1197,Asinex-1705和Asinex-1710具有高度稳定性,涉及铅分子结合时从开放到闭合的构象转变以及活性口袋镁对抑制剂结合和结合的雄辩作用。动作。反复观察到Asp192-Asp208序列区域中覆盖基序β-转角,β-发夹和β-折叠的局部二级结构元素的相互转换,这很可能是在闭合构象事件或镁驱动下该区域排出的压力抑制剂调整。结合自由能估计法预测了所有三种配合物的气相能,其中主要由范德华能量贡献(在Asinex-1705和Asinex-1710的情况下),而在静电和范德华两者的平衡作用下(在Asinex的情况下) -1197)。关键残基扫描入围的Leu45,Asp185,Gy188,Arg231和Lys255在镁和抑制剂在结合位点的相互作用网络中至关重要。通过以下方式重申了它们在净结合能中的关键作用 反复观察到β-折叠,这很可能是在闭合构象事件或镁驱动的抑制剂调整过程中该区域的压力排出的。结合自由能估计法预测了所有三种配合物的气相能,其中主要由范德华能量贡献(在Asinex-1705和Asinex-1710的情况下),而在静电和范德华两者的平衡作用下(在Asinex的情况下) -1197)。关键残基扫描入围的Leu45,Asp185,Gy188,Arg231和Lys255在镁和抑制剂在结合位点的相互作用网络中至关重要。通过以下方式重申了它们在净结合能中的关键作用 反复观察到β-折叠,这很可能是在闭合构象事件或镁驱动的抑制剂调整过程中该区域的压力排出的。结合自由能估计法预测了所有三种配合物的气相能,其中主要由范德华能量贡献(在Asinex-1705和Asinex-1710的情况下),而在静电和范德华两者的平衡作用下(在Asinex的情况下) -1197)。关键残基扫描入围的Leu45,Asp185,Gy188,Arg231和Lys255在镁和抑制剂在结合位点的相互作用网络中至关重要。通过以下方式重申了它们在净结合能中的关键作用 结合自由能估计法预测了所有三种配合物的气相能,其中主要由范德华能量贡献(在Asinex-1705和Asinex-1710的情况下),而在静电和范德华两者的平衡作用下(在Asinex的情况下) -1197)。关键残基扫描入围的Leu45,Asp185,Gy188,Arg231和Lys255在镁和抑制剂在结合位点的相互作用网络中至关重要。通过以下方式重申了它们在净结合能中的关键作用 结合自由能估计法预测了所有三种配合物的气相能,其中主要由范德华能量贡献(在Asinex-1705和Asinex-1710的情况下),而在静电和范德华两者的平衡作用下(在Asinex的情况下) -1197)。关键残基扫描入围的Leu45,Asp185,Gy188,Arg231和Lys255在镁和抑制剂在结合位点的相互作用网络中至关重要。通过以下方式重申了它们在净结合能中的关键作用 Lys255和镁在结合位点与抑制剂的相互作用网络中至关重要。通过以下方式重申了它们在净结合能中的关键作用 Lys255和镁在结合位点与抑制剂的相互作用网络中至关重要。通过以下方式重申了它们在净结合能中的关键作用在计算机现场定向丙氨酸扫描法。过滤后的结果可能对进一步添加支架和结构优化以产生KdsC酶的高亲和力结合物有用,后者的抑制作用反过来会破坏外膜的合成。

更新日期:2020-05-07
down
wechat
bug