Abstract：
The eukaryotic fungal species Candida albicans is a critical infective pathogenic agent. The β-amino acid, Icofungipen, is an effective inhibitor of Candida albicans. Icofungipen binds at the active site of the isoleucyl tRNA synthetase (IleRS) from Candida albicans (CaIleRS) and halts protein translation in fungus. In the present work, we have investigated the mechanism of binding of Icogungipen (abbreviated as IFP). Molecular dynamics (MD) simulations show that the carboxylic acid group of IFP in the CaIleRS: IFP complex is more oriented towards the Connective Polypeptide (CP) core loop compared to the carboxylic acid group of Ile in the CaIleRS: Ile complex. The Arg 410 of the CP core loop near the substrate is extended towards the IFP. Due to the difference in the conformation of residues of the CP core loop, the KMSKR loop is more proximal to the CP core loop in CaIleRS: IFP. The editing domain which is covalently linked with the CP core loop in the CaIleRS: IFP complex is also oriented in such a way that the active site cavity is narrow and longer. The metadynamics calculation shows that the IFP is trapped in a deeper potential well compared to Ile which is due to the effective closure of the gateway of the active site by KMSKR and CP core loop. The thin, long shape of the active site and the closed gate of the active site in CaIleRS: IFP complex is responsible for the effective capture of IFP relative to Ile in the active site.Communicated by Ramaswamy H. Sarma.
摘要：
真核细胞真菌物种白色念珠菌是关键的感染性病原体。β-氨基酸,Icofungipen，是白色念珠菌的有效抑制剂。Icofungipen结合在白色念珠菌（CaIleRS）的异亮氨酸tRNA合成酶（IleRS）的活性位点，并阻止真菌中的蛋白质翻译。在目前的工作中,我们研究了Icogungipen（缩写为IFP）的结合机制。分子动力学(MD)模拟显示,与CaIleRS:Ile复合物中的Ile的羧酸基团相比,CaIleRS:IFP复合物中的IFP的羧酸基团更朝向连接多肽(CP)核心环取向。靠近衬底的CP核心环路的Arg410朝向IFP延伸。由于CP核心环残基构象的差异，在CaIleRS:IFP中,KMSKR环更接近CP核心环。与CaIleRS:IFP复合物中的CP核心环共价连接的编辑结构域也以这样的方式取向,即活性位点腔狭窄且更长。元动力学计算表明，与Ile相比，IFP被困在更深的势阱中，这是由于KMSKR和CP核心回路有效关闭了活动站点的网关。瘦，CaIleRS：IFP复合物中活性位点的长形状和活性位点的闭门负责相对于活性位点中的Ile的IFP的有效捕获。由RamaswamyH.Sarma沟通。
