Laboratory of Molecular Modelling & Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, Genoa 16163, Italy.
J Chem Theory Comput. 2022 Nov 8;18(11):6966-6973. doi: 10.1021/acs.jctc.2c00848. Epub 2022 Oct 6.
Hoogsteen (HG) base pairs have a transient nature and can be structurally similar to Watson-Crick (WC) base pairs, making their occurrence and thermodynamic stability difficult to determine experimentally. Herein, we employed the restrain-free-energy perturbation-release (R-FEP-R) method to calculate the relative free energy of the WC and HG base pairing modes in isolated and bound DNA systems and predict the glycosyl torsion conformational preference of purine bases. Notably, this method does not require prior knowledge of the transition pathway between the two end states. Remarkably, relatively fast convergence was reached, with results in excellent agreement with experimental data for all the examined DNA systems. The R-REP-R method successfully determined the stability of HG base pairing and more generally, the conformational preference of purine bases, in these systems. Therefore, this computational approach can help to understand the dynamic equilibrium between the WC and HG base pairing modes in DNA.
Hoogsteen（HG）碱基对具有瞬态性质，并且在结构上可以与 Watson-Crick（WC）碱基对相似，这使得它们的出现和热力学稳定性难以通过实验来确定。在此，我们采用无约束自由能微扰释放（R-FEP-R）方法来计算孤立和结合 DNA 系统中 WC 和 HG 碱基配对模式的相对自由能，并预测嘌呤碱基的糖苷扭转构象偏好。值得注意的是，该方法不需要事先了解两个终态之间的转变途径。值得注意的是，相对较快地达到了收敛，对于所有检查的 DNA 系统，结果与实验数据非常吻合。R-REP-R 方法成功地确定了 HG 碱基配对的稳定性，更普遍地确定了嘌呤碱基的构象偏好，在这些系统中。因此，这种计算方法可以帮助理解 DNA 中 WC 和 HG 碱基配对模式之间的动态平衡。
