Protein unfolding: Rigidity lost
Protein unfolding: Rigidity lost
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DOI：
10.1073/pnas.062492699
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发表时间：
2002-03-19
影响因子：
11.1
通讯作者：
Thorpe, MF
中科院分区：
文献类型：
--
作者：
Rader, AJ;Hespenheide, BM;Thorpe, MF
我们将蛋白质的展开与其结构稳定性或刚性的丧失联系起来。刚性和柔性是数学和物理学中定义明确的概念，大量定理和算法已成功应用于材料，允许网络中的约束与其可变形性相关。在这里，我们模拟蛋白质解折叠过程中非共价键的减弱或稀释，并确定随着解折叠的进行柔性区域的出现。过渡态由蛋白质的独立键旋转自由度（软盘模式）数量随着其平均原子配位减少而变化的拐点确定。作为平均配位函数的软盘模式分数的一阶导数类似于作为变性剂浓度或温度函数的蛋白质的分数折叠曲线。对于我们研究的 26 种不同蛋白质，二阶导数（一种特定的类热量）显示出在平均配位 (r) = 2.41 附近的峰值。当蛋白质变性时，它在过渡状态下失去刚性，进入只有初始折叠核心保持稳定的状态，然后变得完全变性或柔性。不同结构的蛋白质（包括单体和寡聚体）的这种普遍行为类似于网络玻璃中刚性到软质的相变。这种方法提供了蛋白质和玻璃相变的统一视图，并将平均配位识别为沿着展开路径的相关结构变量或反应坐标。
We relate the unfolding of a protein to its loss of structural stability or rigidity. Rigidity and flexibility are well defined concepts in mathematics and physics, with a body of theorems and algorithms that have been applied successfully to materials, allowing the constraints in a network to be related to its deformability. Here we simulate the weakening or dilution of the noncovalent bonds during protein unfolding, and identify the emergence of flexible regions as unfolding proceeds. The transition state is determined from the inflection point in the change in the number of independent bond-rotational degrees of freedom (floppy modes) of the protein as its mean atomic coordination decreases. The first derivative of the fraction of floppy modes as a function of mean coordination is similar to the fraction-folded curve for a protein as a function of denaturant concentration or temperature. The second derivative, a specific heat-like quantity, shows a peak around a mean coordination of (r) = 2.41 for the 26 diverse proteins we have studied. As the protein denatures, it loses rigidity at the transition state, proceeds to a state where just the initial folding core remains stable, then becomes entirely denatured or flexible. This universal behavior for proteins of diverse architecture, including monomers and oligomers, is analogous to the rigid to floppy phase transition in network glasses. This approach provides a unifying view of the phase transitions of proteins and glasses, and identifies the mean coordination as the relevant structural variable, or reaction coordinate, along the unfolding pathway.