两性离子多肽改善GLP-1生物活性的粗粒化分子模拟

Coarse-Grained Molecular Simulation of Zwitterionic Polypeptides on Improving the Bioactivity of Glucagon-Like Peptide-1(GLP-1)

以胰高血糖素样肽-1(GLP-1)与多肽的混合体系作为研究对象,利用粗粒化分子模拟对其作用模式进行研究。结果显示,3种混合体系都有利于GLP-1形成螺旋结构。其中,两性离子五肽VPKEG具有较强亲水性,在GLP-1周围形成疏松的保护层;而两性离子五肽VPREG与GLP-1形成较多静电作用;对照组五肽VPGAG具有较强疏水性,形成致密聚集体,未能给GLP-1提供足够保护。赖氨酸、谷氨酸组合让两性离子五肽VPKEG具备了恰当的亲疏水性和静电作用,既能维持GLP-1构象,也可避免被免疫蛋白识别,赋予其“隐身”特性。

Zwitterionic polypeptides(ZIPPs)have demonstrated great protection to protein drugs owing for their anti-fouling or“stealth”properties.ZIPPs endow the target protein with better pharmacokinetics than non-zwitterionic counterparts,while the microscopic mechanism is still unclear due to the complicated conformation space.As an alternative,in the present work,we designed three pentapeptides,which share the ZIPP-repeat units VPX1X2G.Here,X1 and X2 are cationic and anionic amino acids,respectively.Glucagon-like peptide-1(GLP-1),an important drug for type-II diabetes,was selected as a research subject,which is mixed with different types of pentapeptides.The interaction mode and conformation space were explored using molecular simulation with coarse-grained PACE(Protein in Atomistic details coupled with Coarse-grained Environment)forcefield.Our molecular simulations revealed that the initially constructedα-helix was quickly destroyed by thermal fluctuation for isolated GLP-1.Finally,only 30%of helix exited in the conformation of GLP-1 and the N-and C-terminus tended to contact each other to form shortβ-sheet.When mixed with pentapeptides,the percent of helical structure increased to about 60%for GLP-1,and the formations of one or two helical segment depended on the interaction mode between pentapeptide and GLP-1.Among them,the zwitterionic pentapeptide VPKEG with the strongest hydrophilicity preferred to be uniformly dispersed in solution,and thus producing a loose protective layer around GLP-1.Because of the arginine residue,the zwitterionic pentapeptide VPREG exerted the strongest electrostatic interaction to GLP-1,which is conducive to the highest helicity of GLP-1 but hardest to the diffusion process.In the control system,pentapeptide VPGAG with the strongest hydrophobicity formed the densest aggregate,but cannot fully enwrapped GLP-1 and provide sufficient protection yet.In short,the same content of lysine and glutamate endows zwitterionic pentapeptide VPKEG with proper hydrophobicity and electrostatic effects,which can not only maintain GLP-1 conformation but also avoid being recognized by immune protein,showing the"stealth"property.In contrast,the arginine residing in VPREG tended to form electrostatic interactions with other residues instead of water molecules,making it not so hydrophilic as VPKEG.