Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore, 560012 Karnataka, India.
Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States.
J Phys Chem B. 2021 Sep 2;125(34):9678-9691. doi: 10.1021/acs.jpcb.1c03779. Epub 2021 Aug 18.
We calculate the rate of dissociation of an insulin dimer into two monomers in water. The rate of this complex reaction is determined by multiple factors that are elucidated. By employing advanced sampling techniques, we first obtain the reaction free energy surface for the dimer dissociation as a function of two order parameters, namely, the distance between the center-of-mass of two monomers () and the number of cross-contacts () among the backbone C atoms of two monomers. We then construct an orthogonal 2D reaction energy surface by introducing the reaction coordinate to denote the minimum energy pathway and a conjugate coordinate that spans the orthogonal direction. The free energy landscape is rugged with multiple maxima and minima. We calculate the rate by employing not only the non-Markovian multidimensional rate theory but also several other theoretical approaches. The necessary reaction frequencies and the frictions are calculated from the time correlation function formalism. Our best estimate of the rate is 0.4 μs. . We gain interesting insights into the dimer dissociation process by looking directly at the trajectories obtained from molecular dynamics simulation.
我们计算了胰岛素二聚体在水中解离为两个单体的速率。该复杂反应的速率由多个因素决定，这些因素已经得到了阐明。通过采用先进的采样技术，我们首先获得了二聚体解离的反应自由能表面，该表面是两个序参量的函数，即两个单体质心之间的距离()和两个单体骨架 C 原子之间的交叉接触数()。然后，我们通过引入反应坐标来构建一个正交的 2D 反应能量表面，表示最小能量途径，并用一个共轭坐标来表示正交方向。自由能景观崎岖不平，有多个最大值和最小值。我们不仅采用非马尔可夫多维速率理论，还采用了其他几种理论方法来计算速率。必要的反应频率和摩擦从时间相关函数形式主义中计算出来。我们对速率的最佳估计是 0.4 μs。我们通过直接观察从分子动力学模拟中获得的轨迹，深入了解二聚体解离过程。
