Curtis Joseph E, Dirama Taner E, Carri Gustavo A, Tobias Douglas J
J Phys Chem B. 2006 Nov 23;110(46):22953-6. doi: 10.1021/jp0615499.
The traditional approach used to predict the ability of a glassy matrix to maximally preserve the activity of a protein solute is the glass transition temperature (T(g)) of the glass. Recently it has been shown that the addition of a low T(g) diluent (glycerol) can rigidify the structure of a high T(g) glassy matrix in binary glycerol-trehalose glasses. The optimal density of glycerol in trehalose minimizes the average mean square displacements of non-exchangeable protons in the glass samples. The amount of glycerol added to a trehalose glass coincides with the maximal recovery of biological activity in a separate study using similar binary glass samples. In this study, we use molecular dynamics (MD) simulations to investigate the dynamics of a hydrated protein encased in glycerol, unary trehalose and binary glycerol-trehalose glasses. We have found that we are able to reproduce the rigidification of the glycerol-trehalose glassy matrix and that there is a direct correlation between bulk glass dynamics and the extent of atomic fluctuation of protein atoms. The detailed microscopic picture that emerges is that protein dynamics are suppressed mainly by inertia of the bulk glass and to a lesser extent specific interactions at the protein-solvent interface. Thus, the inertia of the glassy matrix may be an influential factor in the determination of pharmaceutically relevant formulations.
用于预测玻璃态基质最大程度保留蛋白质溶质活性能力的传统方法是玻璃的玻璃化转变温度（T(g)）。最近有研究表明，添加低T(g)稀释剂（甘油）可使二元甘油-海藻糖玻璃中的高T(g)玻璃态基质结构变硬。海藻糖中甘油的最佳密度可使玻璃样品中不可交换质子的平均均方位移最小化。在另一项使用类似二元玻璃样品的研究中，添加到海藻糖玻璃中的甘油量与生物活性的最大恢复量相符。在本研究中，我们使用分子动力学（MD）模拟来研究包裹在甘油、一元海藻糖和二元甘油-海藻糖玻璃中的水合蛋白质的动力学。我们发现能够重现甘油-海藻糖玻璃态基质的硬化，并且整体玻璃动力学与蛋白质原子的原子波动程度之间存在直接关联。由此呈现的详细微观情况是，蛋白质动力学主要受整体玻璃的惯性抑制，在较小程度上受蛋白质-溶剂界面处的特定相互作用抑制。因此，玻璃态基质的惯性可能是确定药学相关制剂时的一个影响因素。
