Kim Taeho, Rhee Alexander, Yip Christopher M
Chemical Engineering & Applied Chemistry, Institute of Biomaterials & Biomedical Engineering, and The Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON, Canada M5S 3E1.
J Am Chem Soc. 2006 Apr 26;128(16):5330-1. doi: 10.1021/ja0607382.
Understanding the forces and dynamics of insulin dissociation is critical for devising formulations for the treatment of insulin-dependent diabetes. In earlier work, we applied AFM-based force spectroscopy to covalently tethered and oriented insulin monomers to assess the effect of molecular orientation on insulin-insulin binding forces. We report here on steered molecular dynamics simulations of the insulin dissociation force spectroscopy experiment. Consistent with our experiments, our simulation results suggest that insulin dimer dissociation occurs near the limit of extensibility of the B-chain. We have also found that the forced dissociation of the insulin dimer is a rate-dependent process, involving significant conformational changes to the monomer(s). The insulin dimer dissociation pathway also depends on the relative strength of the inter-monomer interactions across the antiparallel beta-sheet interface and the intra-monomer interactions of residues A1 and A30 with the insulin B-chain. Our simulation results strongly support the design of bioactive insulin analogues that involves altering hydrogen bonding and hydrophobic interactions across the beta-sheet dimer interface.
了解胰岛素解离的作用力和动力学对于设计治疗胰岛素依赖型糖尿病的制剂至关重要。在早期工作中，我们将基于原子力显微镜的力谱技术应用于共价连接且定向排列的胰岛素单体，以评估分子取向对胰岛素 - 胰岛素结合力的影响。我们在此报告胰岛素解离力谱实验的引导分子动力学模拟。与我们的实验一致，我们的模拟结果表明胰岛素二聚体解离发生在B链可伸展极限附近。我们还发现胰岛素二聚体的强制解离是一个速率依赖性过程，涉及单体的显著构象变化。胰岛素二聚体的解离途径还取决于跨反平行β - 折叠界面的单体间相互作用以及A1和A30残基与胰岛素B链的单体内部相互作用的相对强度。我们的模拟结果有力地支持了生物活性胰岛素类似物的设计，该设计涉及改变跨β - 折叠二聚体界面的氢键和疏水相互作用。
