Actinonin与肽脱甲酰基酶作用模式的分子动力学模拟研究

Molecular dynamics simulation on the molecular interactions of peptide deformylase and actinonin

目的研究actinonin与脱甲酰基酶的相互作用模式,阐述基于actinonin进行特异性人肽脱甲酰基酶(Hs PDF)抑制剂设计思路。方法使用分子动力学模拟和MM/GBSA自由能计算等方法来研究各种肽脱甲酰基酶(PDF)与actinonin的相互作用模式,定量描述PDF关键残基与actinonin的结合自由能。结果在与actinonin结合方面,Hs PDF作为PDF1A的代表,与PDF1B和PDF2比较,存在3个明显差异:与Hs PDF的motif 1相互作用较强,与motif 2较弱,而与PDF1B和PDF2的motif 1相互作用较弱,而与motif 2相互作用较强;与Hs PDF的Leu131和Met145相互作用较强,而这些相互作用在PDF1B和PDF2是不存在的;与Hs PDF的Trp207存在很强的结合自由能,而与PDF1B和PDF2在相同位置的残基相互作用较弱。结论利用分子动力学模拟的方法,研究actinonin与PDF的相互作用模式,阐述Hs PDF与其他类型PDF在活性位点的差异,为基于actinonin的特异性Hs PDF抑制剂的设计提出了思路。

Objective To investigate the binding modes between actinonin and peptide deformylases and to characterize the informations about how to design the specific Hs PDF inhibitor. Methods The combination of molecular dynamics simulation and MM/GBSA free energy calculation was employed to study the interactions between several PDF enzymes and actinonin. The detailed interactions of each residues of protein and actinonin were calculated by MM/GBSA free energy decomposition. Results Three important differences in actinonin binding to PDFs were obtained as followed:actinonin had stronger binding interaction with the motif 1 of Hs PDF than the motif 2, while actinonin had lower binding interaction with the motif 1 than the motif 2 for PDF1 A and PDF2. Moreover, actinonin had stronger binding affinities with Leu131 and Met145 of Hs PDF, but had no interaction with the corresponding ones of PDF1 A and PDF2. In addition, actinonin interacted strongly with Trp207 of Hs PDF but weakly with the corresponding residue of PDF1 A and PDF2. Conclusion By using the method of molecular dynamics simulation, the interaction of actinonin and PDF model are studied, differences of Hs PDF and PDF in the active site with other types are expounded, based on the design thinking of specific Hs PDF inhibitors of actinonin is proposed.