胰岛素样生长因子及其结合蛋白的作用机理研究

Studies on the interaction of insulin-like growth factor and binding protein

胰岛素样生长因子(insulin-like growth factor,IGF),主要由IGF1和IGF2、胰岛素样生长因子受体(IGF receptor,IGFR)I型和II型,以及胰岛素样生长因子结合蛋白(IGF binding protein,IGFBP)家族组成.实验中发现IGFBP可以抑制IGF2促肿瘤生长的活性,但二者之间的结合位点并不清晰.计算化学可以对蛋白质的结合亲和力进行预测,在药物设计领域中具有非常重要的作用.因此使用分子动力学(molecular dynamics,MD)模拟对IGFBP6与IGF2之间的结合位点进行了扫描式搜索,通过对RMSD(Root Mean-Square Displacement)、相互作用能、有效吸附残基、接触面积等分析,发现IGF2与IGFBP6的结合位点主要集中于C端结构域,其中Arg、Gln、His、Asp、Glu、Asn等极性残基贡献最多,它们主要通过静电相互作用来促进IGFBP6-IGF2复合体系之间的结合.这些结果不仅有助于构建IGFBP6与IGF2二者相互作用的网络图谱,还可以用于推测IGF家族中蛋白质的未知功能,对了解生命活动的本质具有重要意义.

Insulin-like growth factor(IGF),is mainly composed of IGF1 and IGF2,IGF receptor(IGF)I and II,as well as IGF binding protein(IGFBP).It was found that IGFBP can inhibit the growth promoting activity of IGF2 in the experiment,but the interaction between the IGFBP and IGF2 was not clear.Prediction of the binding affinity of proteins is one of the most important applications of computational chemistry in the field of structure-based drug design.Therefore,molecular dynamics was used to study the binding site between IGFBP6 and IGF2.It showed that the binding sites of IGF2 and IGFBP6 mainly focused on the C-terminal domain,and among of Arg,Gln,His,Asp,Glu,Asn and other polar residues contribute most.They can promote the binging of IGFBP6-IGF2 mainly due to electrostatic interactions.These results not only help to construct the network of interaction between IGFBP6 and IGF2,but also can be used to infer the unknown function of protein in IGF family,which is important to understand the significant of life activity.