Simplified protein models: predicting folding pathways and structure using amino acid sequences.
Simplified protein models: predicting folding pathways and structure using amino acid sequences.
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DOI：
10.1103/physrevlett.111.028103
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发表时间：
2013-07-12
影响因子：
8.6
通讯作者：
Sosnick TR
中科院分区：
文献类型：
--
作者：
Adhikari AN;Freed KF;Sosnick TR
我们展示了使用正确制定的模型同时确定蛋白质折叠途径和结构的能力，而无需事先了解天然结构。我们的模型采用自然坐标系来描述蛋白质，并采用了一种搜索策略，该策略的灵感来自于观察到真实蛋白质通过逐渐稳定类似天然的子结构或“折叠子”以顺序方式折叠。最近使用原子分子动力学模拟研究的十二种蛋白质获得了可比的折叠途径和结构[K. Lindorff-Larsen，S.皮亚纳，R.O. Dror, D. E. Shaw, Science 334, 517 (2011)]，我们的计算运行速度快了几个数量级。我们发现，展开状态下的类本地倾向并不一定决定结构形成的顺序，这与 MD 研究的主要结论背道而驰。相反，我们的结果支持更广泛的观点，其中内在的局部结构倾向可能在折叠过程中被环境背景增强或覆盖。我们的搜索策略的成功验证了它是一种在计算机和体内折叠的便捷机制。
We demonstrate the ability of simultaneously determining a protein’s folding pathway and structure using a properly formulated model without prior knowledge of the native structure. Our model employs a natural coordinate system for describing proteins and a search strategy inspired by the observation that real proteins fold in a sequential fashion by incrementally stabilizing native-like substructures or "foldons". Comparable folding pathways and structures are obtained for the twelve proteins recently studied using atomistic molecular dynamics simulations [K. Lindorff-Larsen, S. Piana, R.O. Dror, D. E. Shaw, Science 334, 517 (2011)], with our calculations running several orders of magnitude faster. We find that native-like propensities in the unfolded state do not necessarily determine the order of structure formation, a departure from a major conclusion of the MD study. Instead, our results support a more expansive view wherein intrinsic local structural propensities may be enhanced or overridden in the folding process by environmental context. The success of our search strategy validates it as an expedient mechanism for folding both in silico and in vivo.