Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University in Toruń, ul. Grudziądzka 5, 87-100 Toruń, Poland.
J Chem Inf Model. 2023 Mar 27;63(6):1806-1818. doi: 10.1021/acs.jcim.2c01196. Epub 2023 Feb 6.
Commonly used techniques, such as CryoEM or X-ray, are not able to capture the structural reorganizations of disordered regions of proteins (IDR); therefore, it is difficult to assess their functions in proteins based exclusively on experiments. To fill this gap, we used computational molecular dynamics (MD) simulation methods to capture IDR dynamics and trace biological function-related interactions in the Kir6.2/SUR1 potassium channel. This ATP-sensitive octameric complex, one of the critical elements in the insulin secretion process in human pancreatic β-cells, has four to five large, disordered fragments. Using unique MD simulations of the full Kir6.2/SUR1 channel complex, we present an in-depth analysis of the dynamics of the disordered regions and discuss the possible functions they could have in this system. Our MD results confirmed the crucial role of the N-terminus of the Kir6.2 fragment and the L0-loop of the SUR1 protein in the transfer of mechanical signals between domains that trigger insulin release. Moreover, we show that the presence of IDRs affects natural ligand binding. Our research takes us one step further toward understanding the action of this vital complex.
常用技术，如 CryoEM 或 X 射线，无法捕捉蛋白质无序区域（IDR）的结构重排；因此，仅通过实验很难评估它们在蛋白质中的功能。为了填补这一空白，我们使用计算分子动力学（MD）模拟方法来捕捉 IDR 动力学，并追踪 Kir6.2/SUR1 钾通道中与生物学功能相关的相互作用。这种 ATP 敏感的八聚体复合物是人类胰腺β细胞胰岛素分泌过程中的关键元素之一，有四个到五个大的、无序的片段。通过对完整的 Kir6.2/SUR1 通道复合物进行独特的 MD 模拟，我们对无序区域的动力学进行了深入分析，并讨论了它们在该系统中可能具有的功能。我们的 MD 结果证实了 Kir6.2 片段的 N 端和 SUR1 蛋白的 L0 环在触发胰岛素释放的域间机械信号传递中的关键作用。此外，我们表明 IDRs 的存在会影响天然配体的结合。我们的研究使我们更进一步地了解了这个重要复合物的作用。
