Department of Biochemistry, University of Toronto, Toronto, ON, Canada M5S 1A8.
Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):20919-24. doi: 10.1073/pnas.1209891109. Epub 2012 Dec 3.
Fundamental relationships between the thermodynamics and kinetics of protein folding were investigated using chain models of natural proteins with diverse folding rates by extensive comparisons between the distribution of conformations in thermodynamic equilibrium and the distribution of conformations sampled along folding trajectories. Consistent with theory and single-molecule experiment, duration of the folding transition paths exhibits only a weak correlation with overall folding time. Conformational distributions of folding trajectories near the overall thermodynamic folding/unfolding barrier show significant deviations from preequilibrium. These deviations, the distribution of transition path times, and the variation of mean transition path time for different proteins can all be rationalized by a diffusive process that we modeled using simple Monte Carlo algorithms with an effective coordinate-independent diffusion coefficient. Conformations in the initial stages of transition paths tend to form more nonlocal contacts than typical conformations with the same number of native contacts. This statistical bias, which is indicative of preferred folding pathways, should be amenable to future single-molecule measurements. We found that the preexponential factor defined in the transition state theory of folding varies from protein to protein and that this variation can be rationalized by our Monte Carlo diffusion model. Thus, protein folding physics is different in certain fundamental respects from the physics envisioned by a simple transition-state picture. Nonetheless, transition state theory can be a useful approximate predictor of cooperative folding speed, because the height of the overall folding barrier is apparently a proxy for related rate-determining physical properties.
使用具有不同折叠速率的天然蛋白质的链模型，通过在热力学平衡时的构象分布与折叠轨迹中采样的构象分布之间的广泛比较，研究了蛋白质折叠的热力学和动力学之间的基本关系。与理论和单分子实验一致，折叠过渡路径的持续时间与整体折叠时间仅表现出微弱的相关性。在整体热力学折叠/去折叠势垒附近的折叠轨迹的构象分布显示出与预平衡的显著偏差。这些偏差、过渡路径时间的分布以及不同蛋白质的平均过渡路径时间的变化，都可以通过我们使用具有有效坐标独立扩散系数的简单蒙特卡罗算法建模的扩散过程来合理化。过渡路径初始阶段的构象比具有相同数量天然接触的典型构象更容易形成更多的非局部接触。这种统计偏差表明了优先的折叠途径，应该能够进行未来的单分子测量。我们发现，折叠的过渡态理论中定义的指数前因子在不同蛋白质之间有所不同，而这种变化可以通过我们的蒙特卡罗扩散模型来合理化。因此，蛋白质折叠物理学在某些基本方面与简单过渡态图像所设想的物理学不同。尽管如此，过渡态理论仍然可以作为合作折叠速度的有用近似预测器，因为整体折叠势垒的高度显然是相关速率决定物理性质的代理。
