Metal-coupled folding of Cys2His2 zinc-finger
Metal-coupled folding of Cys2His2 zinc-finger
复制标题
Cys2His2 锌指的金属耦合折叠
DOI：
10.1021/ja075302g
复制
发表时间：
2008-01-23
影响因子：
15
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Li, Wenfei;Zhang, Jian;Wang, Wei
锌指广泛存在于真核细胞中，在生命过程中起着至关重要的作用，其正常折叠依赖于锌离子的结合。为了计算研究锌指的锌耦合折叠，必须考虑电荷转移和金属诱导的质子化/去质子化效应。在这里，通过尝试在经典分子动力学中隐含地解释这种影响，并对有锌结合和没有锌结合的肽进行明确的溶剂模拟，我们研究了Cys(2)His(2)型锌指基序的折叠以及肽折叠与锌结合之间的耦合。我们发现锌离子不仅稳定了天然结构，而且参与了整个折叠过程。它在折叠的早期阶段与肽结合，并指导或调节β -发夹和a-螺旋成分的折叠和稳定。锌结合的这种关键作用是由保守疏水残基的填料介导的。我们还发现疏水残基的包装和天然配体的配位是耦合的。同时，研究了锌结合、错连、配体交换、锌诱导二级结构转化的过程以及锌离子参与下的水行为。我们的结果与相关的实验观察结果很好地一致，并为金属辅因子依赖的蛋白质折叠和其他金属诱导的具有生物学重要性的构象变化的一般机制提供了重要的见解。
Zinc-fingers, which widely exist in eukaryotic cell and play crucial roles in life processes, depend on the binding of zinc ion for their proper folding. To computationally study the zinc-coupled folding of the zinc-fingers, charge transfer and metal induced protonation/deprotonation effects have to be considered. Here, by attempting to implicitly account for such effects in classical molecular dynamics and performing intensive simulations with explicit solvent for the peptides with and without zinc binding, we investigate the folding of the Cys(2)His(2)-type zinc-finger motif and the coupling between the peptide folding and zinc binding. We find that zinc ion not only stabilizes the native structure but also participates in the whole folding process. It binds to the peptide at an early stage of folding and directs or modulates the folding and stabilizations of the component beta-hairpin and a-helix. Such a crucial role of zinc binding is mediated by the packing of the conserved hydrophobic residues. We also find that the packing of the hydrophobic residues and the coordination of the native ligands are coupled. Meanwhile, the processes of zinc binding, mis-ligation, ligand exchange, and zinc induced secondary structure conversion as well as the water behavior due to the involvement of zinc ion are characterized. Our results are in good agreement with related experimental observations and provide significant insight into the general mechanisms of the metal cofactor dependent protein folding and other metal-induced conformational changes of biological importance.