Bueno Marta, Camacho Carlos J, Sancho Javier
Department of Computational Biology, University of Pittsburgh, Pennsylvania, USA.
Proteins. 2007 Sep 1;68(4):850-62. doi: 10.1002/prot.21453.
The bioinformatics revolution of the last decade has been instrumental in the development of empirical potentials to quantitatively estimate protein interactions for modeling and design. Although computationally efficient, these potentials hide most of the relevant thermodynamics in 5-to-40 parameters that are fitted against a large experimental database. Here, we revisit this longstanding problem and show that a careful consideration of the change in hydrophobicity, electrostatics, and configurational entropy between the folded and unfolded state of aliphatic point mutations predicts 20-30% less false positives and yields more accurate predictions than any published empirical energy function. This significant improvement is achieved with essentially no free parameters, validating past theoretical and experimental efforts to understand the thermodynamics of protein folding. Our first principle analysis strongly suggests that both the solute-solute van der Waals interactions in the folded state and the electrostatics free energy change of exposed aliphatic mutations are almost completely compensated by similar interactions operating in the unfolded ensemble. Not surprisingly, the problem of properly accounting for the solvent contribution to the free energy of polar and charged group mutations, as well as of mutations that disrupt the protein backbone remains open.
过去十年的生物信息学革命推动了经验势的发展，以定量估计蛋白质相互作用，用于建模和设计。尽管这些势在计算上效率很高，但它们将大部分相关热力学隐藏在5到40个参数中，这些参数是根据一个大型实验数据库拟合得出的。在此，我们重新审视这个长期存在的问题，并表明仔细考虑脂肪族点突变折叠态与未折叠态之间疏水性、静电和构象熵的变化，预测的假阳性比任何已发表的经验能量函数少20%-30%，且预测更准确。这一显著改进几乎在没有自由参数的情况下实现，验证了过去理解蛋白质折叠热力学的理论和实验努力。我们的第一性原理分析强烈表明，折叠态中的溶质-溶质范德华相互作用以及暴露的脂肪族突变的静电自由能变化几乎完全被未折叠集合中类似的相互作用所补偿。毫不奇怪，正确考虑溶剂对极性和带电基团突变以及破坏蛋白质主链突变的自由能贡献的问题仍然存在。
