Insulin dimer dissociation in aqueous solution: A computational study of free energy landscape and evolving microscopic structure along the reaction pathway
Insulin dimer dissociation in aqueous solution: A computational study of free energy landscape and evolving microscopic structure along the reaction pathway
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DOI：
10.1063/1.5042290
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发表时间：
2018-09-21
影响因子：
4.4
通讯作者：
Bagchi, Biman
中科院分区：
文献类型：
--
作者：
Banerjee, Puja;Mondal, Sayantan;Bagchi, Biman
胰岛素二聚体解离成两个单体是一个重要的生命过程。虽然单体是激素的生物活性形式，但它以六聚体形式储存在胰腺的β细胞中。当需要时，后者解离成二聚体，二聚体又解离成单体，以维持激素的内源性传递。为了在分子水平上理解胰岛素二聚体的解离，我们使用两个顺序参数和蛋白质在显式水中的全原子模型，对胰岛素二聚体在水中的解离进行了有偏差的分子动力学模拟（在良好回火系中的平行回火元动力学）。选择的两个序参数（经过适当的研究）是两个单体的质心之间的距离（R-MM）和两个单体的主- c α原子之间的接触数（N-MM）。我们计算了自由能格局作为这两个阶参数的函数，并确定了解离的最小自由能途径。我们发现该路径涉及多个最小值和多个障碍。在解离初期，单体间的距离变化不大，但N-MM迅速减小。在分离的后期，情况正好相反，即距离R-MM几乎以恒定的低值N-MM增加。由于熵的原因，形成的两种单体蛋白的构型有些不同。水被认为在解离过程中起关键作用，稳定中间产物沿着反应路径。我们的研究揭示了解离过程中有趣的分子细节，如氨基酸残基沿着最小能量路径的结构和相对取向排列的变化。详细研究了胰岛素单体在稳定二聚体和中间二聚体解离过程中的构象变化。AIP出版社出版。
The dissociation of an insulin dimer to two monomers is an important life process. Although the monomer is the biologically active form of the hormone, it is stored in the beta-cells of the pancreas in the hexameric form. The latter, when the need comes, dissociates to dimers and the dimers in turn to monomers to maintain the endogenous delivery of the hormone. In order to understand insulin dimer dissociation at a molecular level, we perform biased molecular dynamics simulations (parallel tempering metadynamics in the well-tempered ensemble) of the dissociation of the insulin dimer in water using two order parameters and an all-atom model of the protein in explicit water. The two order parameters selected (after appropriate studies) are the distance (R-MM ) between the center of mass of two monomers and the number of contacts (N-MM) among the backbone-C alpha atoms of the two monomers. We calculated the free energy landscape as a function of these two order parameters and determined the minimum free energy pathway of dissociation. We find that the pathway involves multiple minima and multiple barriers. In the initial stage of dissociation, the distance between the monomers does not change significantly but the N-MM decreases rapidly. In the latter stage of separation, the opposite occurs, that is, the distance R-MM increases at nearly a constant low value of N-MM. The configurations of the two monomeric proteins so formed are found to be a bit different due to the entropic reasons. Water is seen to play a key role in the dissociation process stabilizing the intermediates along the reaction path. Our study reveals interesting molecular details during the dissociation, such as the variation in the structural and relative orientational arrangement of the amino acid residues along the minimum energy path. The conformational changes of monomeric insulin in the stable dimer and in the intermediate states during dimer dissociation have been studied in detail. Published by AIP Publishing.