How Hydrophobicity and the Glycosylation Site of Glycans Affect Protein Folding and Stability: A Molecular Dynamics Simulation
How Hydrophobicity and the Glycosylation Site of Glycans Affect Protein Folding and Stability: A Molecular Dynamics Simulation
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聚糖的疏水性和糖基化位点如何影响蛋白质折叠和稳定性：分子动力学模拟
DOI：
10.1021/jp203926r
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发表时间：
2012-01-12
影响因子：
3.3
通讯作者：
Liu, Zheng
中科院分区：
文献类型：
--
作者：
Lu, Diannan;Yang, Cheng;Liu, Zheng
糖基化是蛋白质生物合成中最常见的翻译后修饰之一，但其对蛋白质折叠和稳定的构象转变的影响尚不清楚。在这项研究中，我们提出了一个粗粒的离晶格46- β桶模型蛋白质，由具有不同疏水性和糖基化位点的聚糖糖基化，使用朗格万动力学模拟来研究聚糖对蛋白质折叠和稳定的影响，其中提出了一个H项作为聚糖疏水性的指标。与天然蛋白相比，在该模型蛋白的柔性肽残基上引入合适疏水性（0.1 < H < 0.4）的聚糖，不仅促进了蛋白质的折叠，而且显著提高了其构象稳定性。相反，当在蛋白质的限制性肽残基上引入聚糖时，只有亲水性（H = 0）或极弱疏水性（H < 0.2）的聚糖对蛋白质的稳定性略有贡献，但由于自由能垒的增加而阻碍了蛋白质的折叠。糖基化蛋白在疏水崩溃和结构重排方面保持了两步折叠机制。位于适当疏水性位置的聚糖链有利于坍塌和重排，而其他链虽然加速坍塌，但阻碍重排。除了熵效应，即缩小折叠态构象的空间外，在合适的糖基化位点存在疏水性合适的聚糖，通过疏水相互作用，即焓效应，加强了折叠态。模拟显示了糖基化的稳定和不稳定效应，正如文献中实验报道的那样，并提供了糖基化蛋白质的分子洞察力。本研究试图了解不同疏水性聚糖对蛋白质折叠和稳定性的影响，不仅有助于解释实际糖蛋白的稳定和不稳定作用，而且有助于设计用于生物技术目的的蛋白质-聚合物偶联物。
Glycosylation is one of the most common post-translational modifications in the biosynthesis of protein, but its effect on the protein conformational transitions underpinning folding and stabilization is poorly understood. In this study, we present a coarse-grained off-lattice 46-beta barrel model protein glycosylated by glycans with different hydrophobicity and glycosylation sites to examine the effect of glycans on protein folding and stabilization using a Langevin dynamics simulation, in which an H term was proposed as the index of the hydrophobicity of glycan. Compared with its native counterpart, introducing glycans of suitable hydrophobicity (0.1 < H < 0.4) at flexible peptide residues of this model protein not only facilitated folding of the protein but also increased its conformation stability significantly. On the contrary, when glycans were introduced at the restricted peptide residues of the protein, only those hydrophilic (H = 0) or very weak hydrophobic (H < 0.2) ones contributed slightly to protein stability but hindered protein folding due to increased free energy barriers. The glycosylated protein retained the two-step folding mechanism in terms of hydrophobic collapse and structural rearrangement. Glycan chains located in a suitable site with an appropriate hydrophobicity facilitated both collapse and rearrangement, whereas others, though accelerating collapse, hindered rearrangement. In addition to entropy effects, that is, narrowing the space of the conformations of the unfolded state, the presence of glycans with suitable hydrophobicity at suitable glycosylation site strengthened the folded state via hydrophobic interaction, that is, the enthalpy effect. The simulations have shown both the stabilization and the destabilization effects of glycosylation, as experimentally reported in the literature, and provided molecular insight into glycosylated proteins. The understanding of the effects of glycans with different hydrophobicities on the folding and stability of protein, as attempted by the present work, is helpful not only to explain the stabilization and destabilization effect of real glycoproteins but also to design protein-polymer conjugates for biotechnological purposes.