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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Impact of chemical heterogeneity on protein self-assembly in water
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Impact of chemical heterogeneity on protein self-assembly in water

机译：化学异质性对水中蛋白质自组装的影响

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Hydrophobicity is thought to underlie self-assembly in biological systems. However, the protein surface comprises hydrophobic and hydrophilic patches, and understanding the impact of such a chemical heterogeneity on protein self-assembly in water is of fundamental interest. Here, we report structural and thermody-namic investigations on the dimer formation of full-length amy-loid-p proteins in water associated with Alzheimer's disease. Spontaneous dimerization process-from the individual diffusive regime at large separations, through the approach stage in which two proteins come close to each other, to the structural adjustment stage toward compact dimer formation-was captured in full atomic detail via unguided, explicit-water molecular dynamics simulations. The integral-equation theory of liquids was then applied to simulated protein structures to analyze hydration thermo-dynamic properties and the water-mediated interaction between proteins. We demonstrate that hydrophilic residues play a key role in initiating the dimerization process. A long-range hydration force of enthalpic origin acting on the hydrophilic residues provides the major thermodynamic force that drives two proteins to approach from a large separation to a contact distance. After two proteins make atomic contacts, the nature of the water-mediated interaction switches from a long-range enthalpic attraction to a short-range entropic one. The latter acts both on the hydrophobic and hydrophilic residues. Along with the direct protein-protein interactions that lead to the formation of intermonomer hydrogen bonds and van der Waals contacts, the water-mediated attraction of entropic origin brings about structural adjustment of constituent monomer proteins toward the formation of a compact dimer structure.
机译：疏水性被认为是生物系统中自组装的基础。然而，蛋白质表面包含疏水性和亲水性斑块，因此了解这种化学异质性对水中蛋白质自组装的影响至关重要。在这里，我们报告了与阿尔茨海默氏病相关的水中全长淀粉样蛋白p蛋白的二聚体形成的结构和热动力学研究。自发的二聚化过程-从大的分离中的个体扩散过程，通过两个蛋白质彼此接近的接近阶段，到向紧凑的二聚体形成的结构调整阶段-通过未指导的显性水分子以完整的原子细节捕获动力学模拟。然后将液体的积分方程理论应用于模拟的蛋白质结构，以分析水合热力学性质以及蛋白质之间水介导的相互作用。我们证明亲水残基在引发二聚过程中起关键作用。焓起源于亲水性残基的远距离水合作用力提供了主要的热力学力，该力驱使两种蛋白质从较大的距离接近接触距离。在两种蛋白质发生原子接触后，水介导的相互作用的性质从远距离的焓吸引转换为近距离的熵吸引。后者同时作用于疏水和亲水残基。除了导致单体间氢键和范德华接触形成的直接蛋白质-蛋白质相互作用外，水介导的熵源引力还导致组成单体蛋白质的结构调整趋向于形成紧凑的二聚体结构。

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