Ghosh Kingshuk, Ozkan S Banu, Dill Ken A
Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, USA.
J Am Chem Soc. 2007 Oct 3;129(39):11920-7. doi: 10.1021/ja066785b. Epub 2007 Sep 7.
More than a dozen proteins are known to be ultrafast folders. In addition to being fast, their kinetics is unusual. Like traditional rate processes, fast folding proteins have activation barriers at low temperatures, but unlike traditional processes, they have negative activation energies at high temperatures. We develop a model of ultrafast folders that joins a macroscopic mass-action model with a microscopic energy landscape description; we call it the Thruway Search Model. We find good agreement with experimental rates and equilibria on 13 ultrafast folders. The observed folding rates are found to be proportional to the number of microscopic folding routes: fast-folding proteins have more parallel microscopic routes on energy landscapes. At high temperatures, where traditional barriers are small, the remaining bottleneck is a search through denatured conformations to find thruway routes to the native state. Negative activation arises because increasing temperature expands the denatured ensemble, broadening the search, slowing the folding to the native state. We find that the upper estimate of the free energy barriers are positive but small, as little as 0.5 kT.
已知有十几种蛋白质是超快折叠蛋白。除了折叠速度快之外，它们的动力学也很不寻常。与传统的速率过程一样，快速折叠蛋白在低温下有活化能垒，但与传统过程不同的是，它们在高温下具有负活化能。我们开发了一个超快折叠蛋白模型，该模型将宏观质量作用模型与微观能量景观描述相结合；我们称之为高速公路搜索模型。我们发现该模型与13种超快折叠蛋白的实验速率和平衡结果吻合良好。观察到的折叠速率与微观折叠路径的数量成正比：快速折叠蛋白在能量景观上有更多平行的微观路径。在高温下，传统的能垒较小，剩下的瓶颈是通过变性构象进行搜索，以找到通往天然状态的高速公路路径。负活化能的出现是因为温度升高会扩大变性集合，拓宽搜索范围，减慢向天然状态的折叠速度。我们发现自由能垒的上限是正的，但很小，低至0.5 kT。
