Cárdenas Alfredo E, Elber Ron
Department of Computer Science, Cornell University, Ithaca, New York 14853, USA.
Proteins. 2003 May 1;51(2):245-57. doi: 10.1002/prot.10349.
The vast range of time scales (from nanoseconds to seconds) during protein folding is a challenge for experiments and computations. To make concrete predictions on folding mechanisms, atomically detailed simulations of protein folding, using potentials derived from chemical physics principles, are desired. However, due to their computational complexity, straightforward molecular dynamics simulations of protein folding are impossible today. An alternative algorithm is used that makes it possible to compute approximate atomically detailed long time trajectories (the Stochastic Difference Equation in Length). This algorithm is used to compute 26 atomically detailed folding trajectories of cytochrome c (a millisecond process). The early collapse of the protein chain (with marginal formation of secondary structure), and the earlier formation of the N and C helices (compare to the 60's helix) are consistent with the experiment. The existence of an energy barrier upon entry to the molten globule is examined as well. In addition to (favorable) comparison to experiments, we show that non-native contacts drive the formation of the molten globule. In contrast to popular folding models, the non-native contacts do not form off-pathway kinetic traps in cytochrome c.
蛋白质折叠过程中广泛的时间尺度（从纳秒到秒）对实验和计算来说都是一项挑战。为了对折叠机制做出具体预测，需要使用基于化学物理原理的势能对蛋白质折叠进行原子层面详细的模拟。然而，由于其计算复杂性，目前直接进行蛋白质折叠的分子动力学模拟是不可能的。我们使用了一种替代算法，使得计算近似的原子层面详细的长时间轨迹（长度上的随机差分方程）成为可能。该算法用于计算细胞色素c的26条原子层面详细的折叠轨迹（一个毫秒级过程）。蛋白质链的早期塌缩（二级结构形成较少）以及N螺旋和C螺旋的较早形成（与60年代的螺旋相比）与实验结果一致。同时也研究了进入熔球态时能量屏障的存在情况。除了与实验进行（有利的）比较外，我们还表明非天然接触驱动了熔球态的形成。与流行的折叠模型不同，非天然接触在细胞色素c中不会形成非途径动力学陷阱。
