Ha Yuna, Jang Mihee, Lee Sehan, Lee Jee-Young, Lee Woo Cheol, Bae Seri, Kang Jihee, Han Minwoo, Kim Yangmee
Department of Bioscience and Biotechnology, Konkuk University, Seoul, 05029, South Korea.
New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, 41061, South Korea.
J Mol Graph Model. 2020 Nov;100:107669. doi: 10.1016/j.jmgm.2020.107669. Epub 2020 Jul 8.
Acinetobacter baumannii is a gram-negative bacterium that is rapidly developing drug resistance due to the abuse of antibiotics. The emergence of multidrug-resistant A. baumannii has greatly contributed to the urgency of developing new antibiotics. Previously, we had discovered two potent inhibitors of A. baumannii β-ketoacyl acyl carrier protein synthase III (abKAS III), YKab-4 and YKab-6, which showed potent activity against A. baumannii. In addition, we have reported the crystal structure of abKAS III. In the present study, we investigated the binding between abKAS III and its inhibitors by docking simulation. Molecular dynamics (MD) simulations were performed using docked inhibitor models to identify the hotspot residues related to inhibitor binding. The binding free energies estimated using the MD simulations suggest that residues I198 and F260 of abKAS III serve as the inhibitor binding hotspots. I198, found to be responsible for mediating hydrophobic interactions with inhibitors, had the strongest residual binding energy among all abKAS III residues. We modeled glutamine substitutions of residues I198 and F260 and estimated the relative binding energies of the I198Q and F260Q variants. The results confirmed that I198 and F260 are the key inhibitor binding residues. The roles of the key residues in inhibitor binding, i.e. F260 in the α9 helix and the I198 in the β6β7 loop region, were investigated using principal component analysis (PCA). PCA revealed the structural changes resulting from the abKAS III I198Q and F260Q mutations and described the essential dynamics of the α9 helix. In addition, the results suggest that the β6β7 loop region may act as a gate keeper for ligand binding. Hydrophobic interactions involving I198 and F260 in abKAS III appear to be essential for the binding of the inhibitors YKab-4 and YKab-6. In conclusion, this study provides valuable information for the rational design of antibiotics via the inhibition of abKAS III.
鲍曼不动杆菌是一种革兰氏阴性菌，由于抗生素的滥用，其耐药性正在迅速发展。多重耐药鲍曼不动杆菌的出现极大地凸显了开发新型抗生素的紧迫性。此前，我们发现了两种针对鲍曼不动杆菌β-酮酰基酰基载体蛋白合成酶III（abKAS III）的强效抑制剂YKab-4和YKab-6，它们对鲍曼不动杆菌表现出强效活性。此外，我们还报道了abKAS III的晶体结构。在本研究中，我们通过对接模拟研究了abKAS III与其抑制剂之间的结合。使用对接抑制剂模型进行分子动力学（MD）模拟，以识别与抑制剂结合相关的热点残基。通过MD模拟估计的结合自由能表明，abKAS III的I198和F260残基是抑制剂结合热点。发现I198负责介导与抑制剂的疏水相互作用，在所有abKAS III残基中具有最强的残余结合能。我们对I198和F260残基的谷氨酰胺取代进行了建模，并估计了I198Q和F260Q变体的相对结合能。结果证实I198和F260是关键的抑制剂结合残基。使用主成分分析（PCA）研究了关键残基在抑制剂结合中的作用，即α9螺旋中的F260和β6β7环区域中的I198。PCA揭示了abKAS III I198Q和F260Q突变导致的结构变化，并描述了α9螺旋的基本动力学。此外，结果表明β-6β-7环区域可能作为配体结合的守门人。abKAS III中涉及I198和F260的疏水相互作用似乎对于抑制剂YKab-4和YKab-6的结合至关重要。总之，本研究为通过抑制abKAS III合理设计抗生素提供了有价值的信息。
