Folding a protein in a computer:: An atomic description of the folding/unfolding of protein A
Folding a protein in a computer:: An atomic description of the folding/unfolding of protein A
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DOI：
10.1073/pnas.2335541100
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发表时间：
2003-11-25
影响因子：
11.1
通讯作者：
Onuchic, JN
中科院分区：
文献类型：
--
作者：
García, AE;Onuchic, JN
我们在原子分辨率下研究了三螺旋束蛋白的折叠机制，包括显式水的影响。使用副本交换分子动力学，我们在很宽的温度范围内进行足够的采样，以获得作为结构反应坐标的函数的自由能，熵和焓表面。模拟从覆盖折叠和展开状态的不同配置开始。由于在自由能表面的所有最小值之间的许多过渡被观察到，自由能势垒和与它们相关的配置的合奏的定量测定现在是可能的。折叠的动力学瓶颈可以从自由能势垒上的结构的热合奏确定，提供动力学确定的过渡态合奏是类似于从自由能势垒确定的。从这些计算中产生了一个机制，将骨架排序，侧链包装，和去溶剂化之间的相互作用。大的phi值不仅来自于主要在过渡态形成的原生接触，而且来自于已经存在于未折叠状态中的在过渡态部分被破坏的接触。
We study the folding mechanism of a three-helix bundle protein at atomic resolution, including effects of explicit water. Using replica exchange molecular dynamics we perform enough sampling over a wide range of temperatures to obtain the free energy, entropy, and enthalpy surfaces as a function of structural reaction coordinates. Simulations were started from different configurations covering the folded and unfolded states. Because many transitions between all minima at the free energy surface are observed, a quantitative determination of the free energy barriers and the ensemble of configurations associated with them is now possible. The kinetic bottlenecks for folding can be determined from the thermal ensembles of structures on the free energy barriers, provided the kinetically determined transition-state ensembles are similar to those determined from free energy barriers. A mechanism incorporating the interplay among backbone ordering, side-chain packing, and desolvation arises from these calculations. Large phi values arise not only from native contacts, which mostly form at the transition state, but also from contacts already present in the unfolded state that are partially destroyed at the transition.