标题： 乙醇对胰岛素二聚体稳定性的影响 显示英文标题

标题： Adverse effect of ethanol on insulin dimer stability

摘要： 酒精被认为对糖尿病有影响，通常认为少量有益，但过量则有害。 原因尚不完全清楚，但已有人质疑乙醇存在下胰岛素寡聚体的稳定性。 我们计算了胰岛素二聚体在水中以及5%和10%水-乙醇混合物中的自由能表面（FES）和解离路径。 我们发现，在乙醇存在下，解离反应的势垒能量降低了约40%，甚至在5%水-乙醇溶液中也是如此。 此外，乙醇引起了反应路径的显著变化。 我们获得了所有三个系统的反应速率和结合能估计值，并且这些结果与之前关于水中胰岛素二聚体解离的实验结果相符。 计算得到的水中FES由于存在多个中间状态，周围是高而宽的过渡态区域，因此表现出崎岖性。 然而，乙醇的存在使崎岖性变得平滑。 我们在所有三个系统中提取了沿最低能量路径的中间状态构象，并分析了乙醇存在下微观结构的变化。 有趣的是，我们在水-乙醇混合物中发现了一个稳定的中间状态，其中单体之间的中心距离约为3纳米，接触顺序参数接近零。 该中间状态由界面处乙醇和水分子的分布稳定，并且显著地有助于降低解离速率常数。 对解离过程中两个单体的溶剂化以及蛋白质偏离天然状态构型进行了分析，以深入了解二聚体解离过程。 显示英文摘要

摘要： Alcohol is widely believed to have an effect on diabetes, often considered beneficial in small amounts but detrimental in excess. The reasons are not fully known but questions have been asked about the stability of insulin oligomers in the presence of ethanol. We compute the free energy surface (FES) and the pathway of insulin dimer dissociation in water and in 5% and 10% water-ethanol mixture. We find that in the presence of ethanol the barrier energy of dissociation reaction decreases by about 40% even in 5% water-ethanol solution. In addition, ethanol induces a significant change in the reaction pathway. We obtain estimates of the rate of reaction and binding energy for all the three systems and those agree well with the previous experimental results for the insulin dimer dissociation in water. The computed FES in water exhibits ruggedness due to the existence of a number of intermediate states surrounded by high and broad transition state region. However, the presence of ethanol smoothens out the ruggedness. We extracted the conformations of the intermediate states along the minimum energy pathway in all the three systems and analyzed the change in microscopic structures in the presence of ethanol. Interestingly, we discover a stable intermediate state in water-ethanol mixtures where the monomers are separated (center-to-center) by about 3 nm and the contact order parameter is close to zero. This intermediate is stabilized by the distribution of ethanol and water molecules at the interface and which, significantly, serves to reduce the dissociation rate constant .The solvation of the two monomers during the dissociation and proteins' departure from native state configuration are analyzed to obtain insight into the dimer dissociation processes.