Water, often termed as the "lubricant of life," is expected to play an active role in navigating protein dissociation-association reactions. In order to unearth the molecular details, we first compute the free-energy surface (FES) of insulin dimer dissociation employing metadynamics simulation, and then carry out analyses of insulin dimerization and dissociation using atomistic molecular-dynamics simulation in explicit water. We select two sets of initial configurations from 1) the dissociated state and 2) the transition state, and follow time evolution using several long trajectories (∼1-2 μs). During the process we not only monitor configuration of protein monomers, but also the properties of water. Although the equilibrium structural properties of water between the two monomers approach bulklike characteristics at a separation distance of ∼5 nm, the dynamics differ considerably. The complex association process is observed to be accompanied by several structural and dynamical changes of the system, such as large-scale correlated water density fluctuations, coupled conformational fluctuation of protein monomers, a dewettinglike transition with the change of intermonomeric distance RMM from ∼4 to ∼2 nm, orientation of monomers and hydrophobic hydration in the monomers. A quasistable, solvent-shared, protein monomer pair (SSPMP) forms at around 2 nm during association process which is a local free-energy minimum having ∼50-60% of native contacts. Simulations starting with arrangements sampled from the transition state (TS) of the dimer dissociation reveal that the final outcome depends on relative orientation of the backbone in the "hotspot" region.

中文翻译：

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水在蛋白质二聚体缔合和解离分子水平上的动态控制。

经常被称为“生命的润滑剂”的水有望在促进蛋白质解离缔合反应中发挥积极作用。为了揭示分子的细节，我们首先使用元动力学模拟来计算胰岛素二聚体解离的自由能表面（FES），然后使用原子分子动力学模拟在显性水中进行胰岛素二聚化和离解的分析。我们从1）离解态和2）过渡态中选择两组初始构型，并使用多个长轨迹（〜1-2μs）跟踪时间演化。在此过程中，我们不仅监视蛋白质单体的构型，而且还监视水的性质。尽管两种单体之间水的平衡结构性质在约5 nm的分离距离处具有类似块状的特性，但动力学差异很大。观察到复杂的缔合过程伴随着系统的一些结构和动力学变化，例如大规模的相关水密度波动，蛋白质单体的耦合构象波动，随着单体间距离RMM从约4到4的变化而发生的类似去湿的转变。约2 nm，单体的取向和单体中的疏水水合。在缔合过程中约2 nm处形成一个准溶剂共享的蛋白质单体对（SSPMP），这是具有约50-60％天然接触的局部自由能最小值。