<br>阐明胰岛素 NPH 制剂中胰岛素-鱼精蛋白结合相互作用和动力学的计算方法,ACS Omega

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阐明胰岛素 NPH 制剂中胰岛素-鱼精蛋白结合相互作用和动力学的计算方法
ACS Omega ( IF 3.7 ) Pub Date : 2024-01-18 , DOI: 10.1021/acsomega.3c08445
Ketan Kumar Rohilla ₁ , Manoj Kumar Pandey ₁

Affiliation

胰岛素 NPH 是一种中效胰岛素。其持久作用是由于当胰岛素与碱性肽鱼精蛋白、锌离子和酚类配体复合时形成微晶悬浮液。尽管分析技术取得了进步，但胰岛素-鱼精蛋白复合物中鱼精蛋白的结合表位和结合模式仍然未知。在这项研究中，我们使用分子对接和分子动力学（MD）模拟等生物信息学工具来计算胰岛素-鱼精蛋白复合物的结合位点和能量学。我们采用了四种天然存在的鱼精蛋白肽，它们独立地与胰岛素 R6 六聚体对接，并对它们进行 200 ns MD 模拟，以观察复合物的动态并估计结合能。发现富含精氨酸的鱼精蛋白肽通过氢键、疏水性和静电相互作用结合在胰岛素六聚体的表面上，计算出的负结合能很好地支持了这种相互作用。结合后胰岛素六聚体的整体结构得以保留，突出了其在复合物中的动态稳定性。此外，复合物中鱼精蛋白肽末端的残基被认为是高度动态的，在模拟结束时保持稳定。

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Computational Approach to Elucidating Insulin–Protamine Binding Interactions and Dynamics in Insulin NPH Formulations

Insulin NPH is an intermediate-acting insulin. Its protracted action profile is due to the formation of microcrystalline suspensions when insulin is complexed with a basic peptide protamine, zinc ion, and phenolic ligands. Despite advancements in analytical techniques, the binding epitope and binding mode of the protamine in the insulin–protamine complex are still unknown. In this study, we used bioinformatics tools such as molecular docking and molecular dynamics (MD) simulations to compute the binding sites and energetics of the insulin–protamine complex. We have taken four naturally occurring protamine peptides that are independently docked with the insulin R6 hexamer and subjected them to 200 ns MD simulations to observe the dynamics of the complexes and estimate the binding energies. The arginine-rich protamine peptides were found to bind on the surface of the insulin hexamer through hydrogen bonding, hydrophobic, and electrostatic interactions well supported by the calculated negative binding energies. The overall structure of the insulin hexamer was retained upon binding, highlighting its dynamic stability in the complex. Furthermore, the residues at the termini of the protamine peptides in the complex were seen to be highly dynamic, which stabilize toward the end of the simulation.

更新日期：2024-01-18

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