Institut für Physikalische und Theoretische Chemie, Universität Regensburg , 93040 Regensburg, Germany.
J Phys Chem B. 2014 Jan 9;118(1):107-14. doi: 10.1021/jp409934q. Epub 2013 Dec 20.
After studying protein denaturation by urea for many decades, conflicting views of the role of the side chains and the backbone have emerged; many results suggest that urea denatures by enhancing the solubility of both the side chains and the backbone, but the frequently applied transfer model (TM) so far ascribes denaturation exclusively to urea's action on the backbone. We use molecular dynamics simulations to rigorously test one of the TM's key assumptions, the proportionality of a molecule's transfer free energy (TFE) and its solvent-accessible surface. The performance of the TM as it is usually implemented turns out to be unsatisfactory, but the proportionality is satisfied very well after an inconsistency in the treatment of the backbone contribution is corrected. This inconsistency has so far gone unnoticed as it was obscured by a compensating error in the side-chain group TFEs used so far. The revised "universal backbone" TM presented in this work shows excellent accuracy in the prediction of experimental m values of a set of 36 proteins. It also settles the conflicting views regarding the role of the side chains because it predicts that both the side chains and the backbone on average contribute favorably to denaturation by urea.
经过几十年对尿素引起的蛋白质变性的研究，侧链和主链的作用出现了相互矛盾的观点；许多结果表明，尿素通过增强侧链和主链的溶解度来使蛋白质变性，但迄今为止，广泛应用的迁移模型（TM）将变性完全归因于尿素对主链的作用。我们使用分子动力学模拟来严格检验 TM 的一个关键假设，即分子的迁移自由能（TFE）与其溶剂可及表面积之间的比例关系。事实证明，通常实施的 TM 性能并不令人满意，但在纠正了对主链贡献的处理不一致后，这种比例关系得到了很好的满足。这种不一致性迄今为止一直没有被注意到，因为迄今为止，它被用于侧链基团 TFE 的补偿误差所掩盖。在这项工作中提出的经过修正的“通用主链”TM 在预测一组 36 种蛋白质的实验 m 值方面具有出色的准确性。它还解决了关于侧链作用的相互矛盾的观点，因为它预测侧链和主链平均都有利于尿素引起的蛋白质变性。
