Laboratorio de Biofisicoquímica, Departamento de Fisicoquímica, Facultad de Química, Universidad Nacional Autónoma de México, México City 04510, México.
Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City 04510, México.
Structure. 2017 Jan 3;25(1):167-179. doi: 10.1016/j.str.2016.11.018.
Kinetic stability is a key parameter to comprehend protein behavior and it plays a central role to understand how evolution has reached the balance between function and stability in cell-relevant timescales. Using an approach that includes simulations, protein engineering, and calorimetry, we show that there is a clear correlation between kinetic stability determined by differential scanning calorimetry and protein thermal flexibility obtained from a novel method based on temperature-induced unfolding molecular dynamics simulations. Thermal flexibility quantitatively measures the increment of the conformational space available to the protein when energy in provided. The (β/α) barrel fold of two closely related by evolution triosephosphate isomerases from two trypanosomes are used as model systems. The kinetic stability-thermal flexibility correlation has predictive power for the studied proteins, suggesting that the strategy and methodology discussed here might be applied to other proteins in biotechnological developments, evolutionary studies, and the design of protein based therapeutics.
动力学稳定性是理解蛋白质行为的关键参数，它在理解进化如何在与细胞相关的时间尺度上达到功能和稳定性之间的平衡方面起着核心作用。我们采用包括模拟、蛋白质工程和量热法在内的方法，表明差示扫描量热法测定的动力学稳定性与基于温度诱导解折叠分子动力学模拟的新型方法获得的蛋白质热柔性之间存在明显的相关性。热柔性定量地衡量了蛋白质在获得能量时可利用的构象空间的增加。我们使用两个来自两种原生动物的进化上密切相关的三磷酸甘油醛异构酶的（β/α）桶状折叠作为模型系统。动力学稳定性-热柔性相关性对所研究的蛋白质具有预测能力，表明这里讨论的策略和方法可能适用于生物技术开发、进化研究和基于蛋白质的治疗药物设计中的其他蛋白质。
