Levy Yaakov, Cho Samuel S, Shen Tongye, Onuchic José N, Wolynes Peter G
Center for Theoretical Biological Physics, and Department of Physics, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2373-8. doi: 10.1073/pnas.0409572102. Epub 2005 Feb 8.
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.
从动力学角度来看，蛋白质折叠已成为理解最为透彻的生化反应之一。漏斗状能量景观是序列进化实现最小受挫的结果，它解释了大多数蛋白质如何高效且稳健地折叠成其功能结构，并能对折叠动力学进行可靠预测。Rop（引物阻遏物）二聚体的折叠情况较为特殊，因为其一些重新设计疏水核心的突变体，其折叠和解折叠速度都比野生型蛋白快得多，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矛盾。我们提出，假设存在一种双漏斗状能量景观，其上有两个对应于不同但相关拓扑结构的盆地，就可以解开Rop折叠之谜。由于分子近乎对称，突变可导致构象转换为近乎简并但不同的拓扑结构，或导致两种拓扑结构的混合。通过全原子建模进一步发现，预测折叠时具有较低自由能垒高度的拓扑结构，能更好地拟合那些具有极快折叠和解折叠速率的突变体的结构。因此，如果Rop实际上存在两种不同但近乎简并的结构，那么非哈蒙德效应就能在能量景观理论中得到理解。对称且规则结构中的突变可能会导致受挫，从而导致简并。
