Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado, USA.
Biophys J. 2012 May 16;102(10):2331-8. doi: 10.1016/j.bpj.2012.04.013. Epub 2012 May 15.
The efficacy of cancer drugs such as cisplatin (Cp) and oxaliplatin (Ox), which covalently bind to DNA to form drug-DNA adducts, is linked to their recognition by repair proteins such as HMGB1a. Previous experimental studies showed that HMGB1a's binding affinity for Cp- and Ox-DNA varies with the drug used and the local DNA sequence context of the adduct. We link this differential binding affinity to the free energy of deforming (bending and minor groove opening) the drug-DNA molecule during HMGB1a binding. Specifically, the minimal binding affinity of HMGB1a for Ox-DNA in the TGGA context is explained by its larger deformation free energy compared with Cp-DNA or Ox-DNA in other sequence contexts. Methyl groups on neighboring thymine bases in Ox-TGGA crowd the minor groove and sterically hinder the motion of the diaminocyclohexane ring of Ox, leading to this reduced deformability and resultant decrease in HMGB1a's binding affinity.
顺铂（Cp）和奥沙利铂（Ox）等癌症药物的疗效与其与 DNA 形成药物-DNA 加合物的能力有关，这与修复蛋白如高迁移率族蛋白 1a（HMGB1a）的识别有关。先前的实验研究表明，HMGB1a 与 Cp- 和 Ox-DNA 的结合亲和力因所用药物和加合物的局部 DNA 序列上下文而异。我们将这种差异结合亲和力与 HMGB1a 结合过程中药物-DNA 分子的变形（弯曲和小沟开口）自由能联系起来。具体来说，HMGB1a 在 TGGA 背景下对 Ox-DNA 的最小结合亲和力可以用其与 Cp-DNA 或其他序列背景下的 Ox-DNA 相比，变形自由能较大来解释。Ox-TGGA 中相邻胸腺嘧啶碱基上的甲基基团使小沟拥挤，并阻碍 Ox 的二氨基环己烷环的运动，导致这种变形性降低，从而降低 HMGB1a 的结合亲和力。
