Department of Chemistry, Stanford University, Stanford, California 94305, United States.
J Am Chem Soc. 2011 Feb 2;133(4):664-7. doi: 10.1021/ja106936n.
Protein folding is a classic grand challenge that is relevant to numerous human diseases, such as protein misfolding diseases like Alzheimer’s disease. Solving the folding problem will ultimately require a combination of theory, simulation, and experiment, with theory and simulation providing an atomically detailed picture of both the thermodynamics and kinetics of folding and experimental tests grounding these models in reality. However, theory and simulation generally fall orders of magnitude short of biologically relevant time scales. Here we report significant progress toward closing this gap: an atomistic model of the folding of an 80-residue fragment of the λ repressor protein with explicit solvent that captures dynamics on a 10 milliseconds time scale. In addition, we provide a number of predictions that warrant further experimental investigation. For example, our model’s native state is a kinetic hub, and biexponential kinetics arises from the presence of many free-energy basins separated by barriers of different heights rather than a single low barrier along one reaction coordinate (the previously proposed incipient downhill folding scenario).
蛋白质折叠是一个经典的重大挑战，与许多人类疾病有关，如阿尔茨海默病等蛋白质错误折叠疾病。解决折叠问题最终需要理论、模拟和实验的结合，理论和模拟提供了折叠热力学和动力学的原子细节图，而实验则将这些模型建立在现实基础上。然而，理论和模拟通常在生物学相关时间尺度上相差几个数量级。在这里，我们报告了在缩小这一差距方面的重大进展：一个带有显式溶剂的 80 残基 λ 阻遏蛋白折叠的原子模型，可以捕捉到 10 毫秒时间尺度上的动力学。此外，我们还提供了一些需要进一步实验研究的预测。例如，我们的模型的天然状态是一个动力学枢纽，双指数动力学源于许多自由能盆地的存在，这些盆地由不同高度的势垒隔开，而不是沿着一个反应坐标存在一个单一的低势垒（以前提出的初始下坡折叠情景）。
