Elcock A H
Department of Biochemistry, University of Iowa, Iowa City, IA 52242-1109, USA.
J Mol Biol. 2001 Sep 28;312(4):885-96. doi: 10.1006/jmbi.2001.5009.
Catalytic and other functionally important residues in proteins can often be mutated to yield more stable proteins. Many of these residues are charged residues that are located in electrostatically unfavorable environments. Here it is demonstrated that because continuum electrostatics methods can identify these destabilizing residues, the same methods can also be used to identify functionally important residues in otherwise uncharacterized proteins. To establish this point, detailed calculations are performed on six proteins for which good structural and mutational data are available from experiments. In all cases it is shown that functionally important residues known to be destabilizing experimentally are among the most destabilizing residues found in the calculations. A larger scale analysis performed on 216 different proteins demonstrates the existence of a general relationship between the calculated electrostatic energy of a charged residue and its degree of evolutionary conservation. This relationship becomes obscured when electrostatic energies are calculated using Coulomb's law instead of the more complete continuum electrostatics method. Finally, in a first predictive application of the method, calculations are performed on three proteins whose structures have recently been reported by a structural genomics consortium.
蛋白质中的催化残基和其他功能重要残基常常可以通过突变来产生更稳定的蛋白质。这些残基中有许多是带电荷的残基，它们处于静电不利的环境中。本文证明，由于连续介质静电学方法能够识别这些使蛋白质不稳定的残基，因此同样的方法也可用于识别其他未表征蛋白质中的功能重要残基。为了说明这一点，对六种蛋白质进行了详细计算，实验已获得了它们良好的结构和突变数据。在所有情况下均表明，实验上已知会使蛋白质不稳定的功能重要残基，在计算中也是最不稳定的残基。对216种不同蛋白质进行的大规模分析表明，带电残基的计算静电能与其进化保守程度之间存在普遍关系。当使用库仑定律而非更完整的连续介质静电学方法计算静电能时，这种关系就变得模糊不清。最后，作为该方法的首次预测性应用，对结构基因组学联盟最近报道了其结构的三种蛋白质进行了计算。
