Stumpe Martin C, Grubmüller Helmut
Department of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
J Am Chem Soc. 2007 Dec 26;129(51):16126-31. doi: 10.1021/ja076216j. Epub 2007 Nov 30.
The molecular mechanism of urea-induced protein denaturation is not yet fully understood. Mainly two opposing mechanisms are controversially discussed, according to which either hydrophobic, or polar interactions are the dominant driving force. To resolve this question, we have investigated the interactions between urea and all 20 amino acids by comprehensive molecular dynamics simulations of 22 tripeptides. Calculation of atomic contact frequencies between the amino acids and solvent molecules revealed a clear profile of solvation preferences by either water or urea. Almost all amino acids showed preference for contacts with urea molecules, whereas charged and polar amino acids were found to have slight preferences for contact with water molecules. Particularly strong preference for contacts to urea were seen for aromatic and apolar side-chains, as well as for the protein backbone of all amino acids. Further, protein-urea hydrogen bonds were found to be significantly weaker than protein-water or water-water hydrogen bonds. Our results suggest that hydrophobic interactions are the dominant driving force, while hydrogen bonds between urea and the protein backbone contribute markedly to the overall energetics by avoiding unfavorable unsatisfied hydrogen bond sites on the backbone. In summary, we suggest a combined mechanism that unifies the two current and seemingly opposing views.
尿素诱导蛋白质变性的分子机制尚未完全明了。目前主要有两种相互对立的机制存在争议，一种认为疏水相互作用起主导作用，另一种则认为极性相互作用是主要驱动力。为解决这一问题，我们通过对22种三肽进行全面的分子动力学模拟，研究了尿素与所有20种氨基酸之间的相互作用。计算氨基酸与溶剂分子之间的原子接触频率，揭示了水或尿素的溶剂化偏好的清晰特征。几乎所有氨基酸都表现出与尿素分子接触的偏好，而带电荷和极性氨基酸则对与水分子接触有轻微偏好。对于芳香族和非极性侧链以及所有氨基酸的蛋白质主链，与尿素接触的偏好尤为强烈。此外，发现蛋白质与尿素之间的氢键明显弱于蛋白质与水或水与水之间的氢键。我们的结果表明，疏水相互作用是主要驱动力，而尿素与蛋白质主链之间的氢键通过避免主链上不利的未满足氢键位点，对整体能量学有显著贡献。总之，我们提出了一种综合机制，统一了目前两种看似对立的观点。
