Structure-based statistical thermodynamic analysis of T4 lysozyme mutants: Structural mapping of cooperative interactions
Structure-based statistical thermodynamic analysis of T4 lysozyme mutants: Structural mapping of cooperative interactions
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DOI：
10.1016/s0301-4622(96)02220-x
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发表时间：
1997-02-28
影响因子：
3.8
通讯作者：
Freire, E
中科院分区：
文献类型：
--
作者：
Hilser, VJ;Townsend, BD;Freire, E
蛋白质折叠能量学的结构参数化的最新发展使得描述焓、熵和热容变化的函数，即吉布斯能量的各个组成部分，被纳入描述平衡条件下构象状态分布的统计热力学形式。这种方法的目标是用计算机构建一个大的构象态集合，然后推导出最可能的总体分布，即最能解释大量实验观测值的状态分布。该分析已应用于4个不同的T4溶菌酶突变体（S44A, S44G, V131A, V131G）。结果表明，结构参数化可以很好地预测蛋白质的稳定性和突变的影响。计算了四个突变体每个残基的整个折叠常数集。在所有情况下，突变的影响通过序列和三维空间传播到突变位点之外。尽管突变发生在溶剂暴露的位置，并且不直接影响蛋白质中的其他相互作用，但这种现象仍会发生。这些结果表明，在溶剂暴露位置的单个氨基酸突变，或引起最小扰动的其他位置，可以用来确定合作相互作用的程度。这些影响的大小和程度以及算法的准确性可以通过核磁共振检测的氢交换来测试。
The recent development of a structural parameterization of the energetics of protein folding has permitted the incorporation of the functions that describe the enthalpy, entropy and heat capacity changes, i.e. the individual components of the Gibbs energy, into a statistical thermodynamic formalism that describes the distribution of conformational states under equilibrium conditions. The goal of this approach is to construct with the computer a large ensemble of conformational states, and then to derive the most probable population distribution, i.e. the distribution of states that best accounts for a wide array of experimental observables. This analysis has been applied to four different mutants of T4 lysozyme (S44A, S44G, V131A, V131G). It is shown that the structural parameterization predicts well the stability of the protein and the effects of the mutations. The entire set of folding constants per residue has been calculated for the four mutants. In all cases, the effect of the mutations propagates beyond the mutation site itself through sequence and three-dimensional space. This phenomenon occurs despite the fact that the mutations are at solvent-exposed locations and do not directly affect other interactions in the protein. These results suggest that single amino acid mutations at solvent-exposed locations, or other locations that cause a minimal perturbation, can be used to identify the extent of cooperative interactions. The magnitude and extent of these effects and the accuracy of the algorithm can be tested by means of NMR-detected hydrogen exchange.