Coarse-Grained Molecular Simulation of Zwitterionic Polypeptides on Improving the Bioactivity of Glucagon-Like Peptide-1(GLP-1)
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摘要: 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。Abstract: 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 constructed α-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 short β-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.
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Key words:
- glucagon-like peptide-1 /
- zwitterionic polypeptide /
- molecular simulation
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图 1 各模拟体系中GLP-1蛋白的二级结构随时间的变化情况
Figure 1. Time evaluation of the secondary structures for GLP-1 protein in different simulated systems
图 2 各模拟体系中五肽的原子接触数（Atomic contact）随时间的变化情况：（a）五肽与水溶剂的接触数；（b）五肽与GLP-1蛋白的接触数
Figure 2. Time evaluation of the atomic contacts for pentapeptides with （a） water and （b） GLP-1 protein in different simulated systems
图 3 热力学平衡后，各模拟体系中GLP-1蛋白的（a）二级结构分布及（b）末端距
Figure 3. （a） Distribution of secondary structures and （b） end-to-end distance of GLP-1 protein in different simulated systems when reaching thermodynamic equilibrium
图 4 热力学平衡后，各模拟体系中GLP-1蛋白的典型构象
Figure 4. Typical conformation of GLP-1 protein in different simulated systems when reaching thermodynamic equilibrium
图 5 （a）五肽在GLP-1周围的径向分布情况；（b）GLP-1各个残基与多肽的原子接触情况
Figure 5. （a） Radial distribution functions （RDF） of around GLP-1; （b） Atomic contacts with pentapeptides for each residue of GLP-1
图 6 各模拟体系中多肽在GLP-1蛋白周围的典型分布
Figure 6. Typical distribution of pentapeptides around GLP-1 protein in different simulated systems
图 7 各模拟体系中静电相互作用情况
Figure 7. The electrostatic interactions among GLP-1 protein and pentapeptides in different simulated systems
图 8 各模拟体系中五肽各残基与GLP-1蛋白的原子接触数
Figure 8. Atomic contacts with GLP-1 for each residue of pentapeptide
图 9 水分子在两性离子多肽特定残基周围的径向分布：（a）赖氨酸及精氨酸侧基N原子周围的水分子分布；（b）谷氨酸侧基O原子周围的水分子分布
Figure 9. Radial distribution of water molecules around some specific residues of zwitterionic pentapeptides: （a） The distribution of water molecules around N atoms of the side groups of LYS and ARG; （b） The distribution of water molecules around the O atom of the side groups of GLU
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