Laboratory of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen 518055, China.
College of Chemistry and Molecular Engineering, Peking University , Beijing 100871, China.
J Chem Theory Comput. 2017 Jan 10;13(1):320-328. doi: 10.1021/acs.jctc.6b00848. Epub 2016 Dec 5.
Site-specific phosphorylation of an intrinsically disordered protein, eIF4E-binding protein isoform 2 (4E-BP2), can suppress its native function by folding it into a four-stranded β-sheet, but the mechanism of this phosphorylation-induced folding is unclear. In this work, we use all-atom molecular dynamics simulations to investigate both the folded and unfolded states of 4E-BP2 under different phosphorylation states of T37 and T46. The results show that the phosphorylated forms of both T37 and T46 play important roles in stabilizing the folded structure, especially for the β-turns and the sequestered binding motif. The phosphorylated residues not only guide the folding of the protein through several intermediate states but also affect the conformational distribution of the unfolded ensemble. Significantly, the phosphorylated residues can function as nucleation sites for the folding of the protein by forming certain local structures that are stabilized by hydrogen bonding involving the phosphate group. The region around phosphorylated T46 appears to fold before that around phosphorylated T37. These findings provide new insight into the intricate effects of protein phosphorylation.
特定位点磷酸化的一种无序蛋白 eIF4E 结合蛋白 2 异构体（4E-BP2），可以通过折叠成四股β-折叠来抑制其天然功能，但这种磷酸化诱导折叠的机制尚不清楚。在这项工作中，我们使用全原子分子动力学模拟研究了 T37 和 T46 不同磷酸化状态下 4E-BP2 的折叠态和无规卷曲态。结果表明，T37 和 T46 的磷酸化形式在稳定折叠结构方面起着重要作用，特别是对β-转角和隐蔽的结合基序。磷酸化残基不仅通过几个中间态引导蛋白质折叠，还影响无规卷曲集合的构象分布。重要的是，磷酸化残基可以通过形成特定的局部结构作为蛋白质折叠的成核位点，这些局部结构通过涉及磷酸基团的氢键稳定。磷酸化 T46 周围的区域似乎比磷酸化 T37 周围的区域先折叠。这些发现为蛋白质磷酸化的复杂影响提供了新的见解。
