Dipartimento di Fisica, Università degli Studi di Trento, Via Sommarive 14, I-38123 Povo, Trento, Italy.
Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2330-5. doi: 10.1073/pnas.1111796109. Epub 2012 Jan 26.
We investigate the folding mechanism of the WW domain Fip35 using a realistic atomistic force field by applying the Dominant Reaction Pathways approach. We find evidence for the existence of two folding pathways, which differ by the order of formation of the two hairpins. This result is consistent with the analysis of the experimental data on the folding kinetics of WW domains and with the results obtained from large-scale molecular dynamics simulations of this system. Free-energy calculations performed in two coarse-grained models support the robustness of our results and suggest that the qualitative structure of the dominant paths are mostly shaped by the native interactions. Computing a folding trajectory in atomistic detail only required about one hour on 48 Central Processing Units. The gain in computational efficiency opens the door to a systematic investigation of the folding pathways of a large number of globular proteins.
我们使用真实的原子力场通过应用主导反应途径方法来研究 WW 结构域 Fip35 的折叠机制。我们发现存在两种折叠途径的证据，这两种途径的区别在于两个发夹形成的顺序不同。这一结果与对 WW 结构域折叠动力学的实验数据分析以及对该系统的大规模分子动力学模拟结果一致。在两个粗粒化模型中进行的自由能计算支持了我们结果的稳健性，并表明主导路径的定性结构主要由天然相互作用决定。在原子细节中计算折叠轨迹仅在 48 个中央处理单元上需要大约一个小时。计算效率的提高为系统研究大量球状蛋白的折叠途径打开了大门。
