Symmetry and frustration in protein energy landscapes: A near degeneracy resolves the Rop dimer-folding mystery
Symmetry and frustration in protein energy landscapes: A near degeneracy resolves the Rop dimer-folding mystery
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DOI：
10.1073/pnas.0409572102
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发表时间：
2005-02-15
影响因子：
11.1
通讯作者：
Wolynes, PG
中科院分区：
文献类型：
--
作者：
Levy, Y;Cho, SS;Wolynes, PG
从动力学的角度来看，蛋白质折叠已经成为最好理解的生化反应之一。漏斗状的能量景观，序列进化所实现的最小挫折的结果，解释了大多数蛋白质如何有效和稳健地折叠到它们的功能结构，并允许强大的预测折叠动力学。Rop（引物阻遏物）二聚体的折叠是例外的，因为它的一些具有重新设计的疏水核心的突变体比WT蛋白折叠和展开快得多，这似乎与拓扑结构主要决定动力学的简单漏斗状能量景观相冲突。我们建议，罗普折叠的奥秘，可以通过假设一个双漏斗的能源景观，有两个盆地，对应于不同的，但相关的拓扑结构，解开。由于分子的近对称性，突变可以导致构象转换为几乎简并但不同的拓扑结构或导致两种拓扑结构的混合物。通过全原子建模进一步发现了预测具有较低折叠自由能势垒高度的拓扑结构，从而为具有极端折叠和解折叠速率的突变体提供了更好的结构拟合。因此，非哈蒙德效应可以在能量景观理论中理解，如果实际上存在两种不同但几乎退化的结构。对称和规则结构中的突变可能引起挫折，从而导致简并。
Protein folding has become one of the best understood biochemical reactions from a kinetic viewpoint. The funneled energy landscape, a consequence of the minimal frustration achieved by evolution in sequences, explains how most proteins fold efficiently and robustly to their functional structure and allows robust prediction of folding kinetics. The folding of Rop (repressor of primer) dimer is exceptional because some of its mutants with a redesigned hydrophobic core both fold and unfold much faster than the WT protein, which seems to conflict with a simple funneled energy landscape for which topology mainly determines the kinetics. We propose that the mystery of Rop folding can be unraveled by assuming a double-funneled energy landscape on which there are two basins that correspond to distinct but related topological structures. Because of the near symmetry of the molecule, mutations can cause a conformational switch to a nearly degenerate yet distinct topology or lead to a mixture of both topologies. The topology predicted to have the lower free-energy barrier height for folding was further found by all-atom modeling to give a better structural fit for those mutants with the extreme folding and unfolding rates. Thus, the non-Hammond effects can be understood within energy-landscape theory if there are in fact two different but nearly degenerate structures for Rop. Mutations in symmetric and regular structures may give rise to frustration and thus result in degeneracy.