Hill John J, Shalaev Evgenyi Y, Zografi George
ICOS Corporation, 22021 20th Avenue SE, Bothell, WA 98021, USA.
J Pharm Sci. 2005 Aug;94(8):1636-67. doi: 10.1002/jps.20333.
The internal, dynamical fluctuations of protein molecules exhibit many of the features typical of polymeric and bulk small molecule glass forming systems. The response of a protein's internal molecular mobility to temperature changes is similar to that of other amorphous systems, in that different types of motions freeze out at different temperatures, suggesting they exhibit the alpha-beta-modes of motion typical of polymeric glass formers. These modes of motion are attributed to the dynamic regimes that afford proteins the flexibility for function but that also develop into the large-scale collective motions that lead to unfolding. The protein dynamical transition, T(d), which has the same meaning as the T(g) value of other amorphous systems, is attributed to the temperature where protein activity is lost and the unfolding process is inhibited. This review describes how modulation of T(d) by hydration and lyoprotectants can determine the stability of protein molecules that have been processed as bulk, amorphous materials. It also examines the thermodynamic, dynamic, and molecular factors involved in stabilizing folded proteins, and the effects typical pharmaceutical processes can have on native protein structure in going from the solution state to the solid state.
蛋白质分子的内部动态波动呈现出许多聚合物和块状小分子玻璃形成系统所特有的特征。蛋白质内部分子流动性对温度变化的响应与其他非晶态系统相似，即不同类型的运动在不同温度下冻结，这表明它们表现出聚合物玻璃形成体典型的α-β运动模式。这些运动模式归因于动态机制，这些机制赋予蛋白质发挥功能的灵活性，但也发展成导致蛋白质展开的大规模集体运动。蛋白质动态转变温度T(d)与其他非晶态系统的T(g)值具有相同含义，它归因于蛋白质活性丧失且展开过程受到抑制的温度。本综述描述了通过水合作用和冻干保护剂对T(d)的调节如何决定作为块状非晶态材料处理的蛋白质分子的稳定性。它还研究了稳定折叠蛋白质所涉及的热力学、动力学和分子因素，以及典型药物过程从溶液态转变为固态时对天然蛋白质结构可能产生的影响。
