Fodor Anthony A, Aldrich Richard W
Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305-5345, USA.
J Biol Chem. 2004 Apr 30;279(18):19046-50. doi: 10.1074/jbc.M402560200. Epub 2004 Mar 15.
The inherent complexity of thermodynamic coupling in proteins presents a major challenge in understanding and engineering protein function. Recent work has argued that the study of proteins can be simplified by the use of correlated mutations in the evolutionary record to locate a small subset of thermodynamically coupled residues that participate in functionally important, evolutionarily conserved energetic pathways. To test this hypothesis, we examined the predictions of correlated mutation algorithms for a number of proteins for which coupling between residues has been determined by analysis of double mutant cycles. We find that correlated mutation algorithms can find residue pairs that are physically close and that physically close residue pairs tend to be thermodynamically coupled. We find little evidence, however, for the hypothesis that thermodynamic coupling is limited to the subset of evolutionarily constrained residue positions.
蛋白质中热力学偶联的内在复杂性给理解和设计蛋白质功能带来了重大挑战。最近的研究认为，通过利用进化记录中的相关突变来定位一小部分参与功能重要、进化保守的能量途径的热力学偶联残基，可以简化对蛋白质的研究。为了验证这一假设，我们检查了相关突变算法对多种蛋白质的预测，这些蛋白质中残基之间的偶联已通过双突变循环分析确定。我们发现相关突变算法可以找到物理距离接近的残基对，并且物理距离接近的残基对往往是热力学偶联的。然而，我们几乎没有找到证据支持热力学偶联仅限于进化受限残基位置子集的假设。
