Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, United Kingdom.
Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21057-62. doi: 10.1073/pnas.1112197108. Epub 2011 Dec 12.
The identification of the factors that enable normally folded proteins to remain in their soluble and functional states is crucial for a comprehensive understanding of any biological system. We have determined a series of energy landscapes of the acylphosphatase from Drosophila melanogaster under a variety of conditions by combining NMR measurements with restrained molecular dynamics simulations. We thus analyzed the differences in the structures, dynamics, and energy surfaces of the protein in its soluble state or in situations where it aggregates through conformational states that have native-like structure, folding stability, and enzymatic activity. The study identifies the nature of the energy barriers that under normal physiological conditions prevent the protein ensemble from populating dangerous aggregation-prone states. We found that such states, although similar to the native conformation, have altered surface charge distribution, alternative topologies of the β-sheet region, and modified solvent exposure of hydrophobic surfaces and aggregation-prone regions of the sequence. The identified barriers allow the protein to undergo functional dynamics while remaining soluble and without a significant risk of misfolding and aggregation into nonfunctional and potentially toxic species.
确定使正常折叠的蛋白质保持可溶性和功能性状态的因素对于全面理解任何生物系统都至关重要。我们通过将 NMR 测量与约束分子动力学模拟相结合，确定了在各种条件下来自黑腹果蝇的酰基磷酸酶的一系列能量景观。因此，我们分析了该蛋白质在可溶性状态下，或在通过具有天然样结构、折叠稳定性和酶活性的构象状态聚集的情况下，在结构、动力学和能量表面上的差异。该研究确定了在正常生理条件下阻止蛋白质整体进入危险的聚集倾向状态的能量障碍的性质。我们发现，尽管这些状态与天然构象相似，但它们具有改变的表面电荷分布、β-折叠区域的替代拓扑结构以及改变的疏水性表面和序列中聚集倾向区域的溶剂暴露。所确定的障碍允许蛋白质在保持可溶性的同时进行功能动力学，而不会有折叠错误和聚集到非功能性和潜在毒性物质的风险。
