Dang L X, Pearlman D A, Kollman P A
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
Proc Natl Acad Sci U S A. 1990 Jun;87(12):4630-4. doi: 10.1073/pnas.87.12.4630.
We have carried out free energy perturbation calculations on DNA double-stranded hexanucleotides. The sequence d(CGCGCG)2 has been "mutated" into d(CGTGCG).d(CGCACG) with the oligonucleotide in the A, B, and Z structural forms, both in vacuo and in aqueous solution. In addition, model free energy calculations have been carried out in which the electrostatic charges of the H-bonding groups of the bases in the major and minor grooves of the DNA are reduced to zero as a way of assessing the relative solvation effects of these groups in the different structural forms of DNA. Finally, energy component analyses have been carried out to assess the relative roles of different intranucleotide interactions on the B----Z equilibrium as a function of base sequence. In vacuo, the free energy for changing a G.C to an A.T base pair is largest in the Z conformation; in the A and B conformations, the free energy cost is approximately 2 kcal/mol lower (1 cal = 4.184 J). The results are similar when the simulations are run in explicit solvent: the change costs 3 kcal/mol more in the Z conformation than in the B form. These results are consistent with experimental data, where it is clear that A.T sequences are significantly more "Z-phobic" than G.C sequences. The calculations indicate that both intranucleotide and solvation interactions contribute to this Z-phobicity.
我们对DNA双链六聚体进行了自由能微扰计算。序列d(CGCGCG)₂已“突变”为d(CGTGCG).d(CGCACG)，该寡核苷酸处于A、B和Z结构形式，计算分别在真空和水溶液中进行。此外，还进行了模型自由能计算，其中DNA大沟和小沟中碱基氢键基团的静电荷被设为零，以此评估这些基团在不同DNA结构形式中的相对溶剂化效应。最后，进行了能量成分分析，以评估不同核苷酸内相互作用对B→Z平衡的相对作用，该平衡是碱基序列的函数。在真空中，将一个G.C碱基对转变为一个A.T碱基对的自由能在Z构象中最大；在A和B构象中，自由能成本大约低2千卡/摩尔（1卡 = 4.184焦耳）。当在显式溶剂中进行模拟时，结果类似：在Z构象中的转变成本比在B构象中高3千卡/摩尔。这些结果与实验数据一致，在实验数据中很明显A.T序列比G.C序列更“怕Z”。计算表明，核苷酸内相互作用和溶剂化相互作用都导致了这种怕Z现象。
