Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, 52425 Jülich, Germany.
Faculty of Mathematics, Computer Science and Natural Sciences, RWTH-Aachen University, 52056 Aachen, Germany.
Nucleic Acids Res. 2018 Dec 14;46(22):11687-11697. doi: 10.1093/nar/gky1082.
Cisplatin is one of the most widely used anticancer drugs. Its efficiency is unfortunately severely hampered by resistance. The High Mobility Group Box (HMGB) proteins may sensitize tumor cells to cisplatin by specifically binding to platinated DNA (PtDNA) lesions. In vivo, the HMGB/PtDNA binding is regulated by multisite post-translational modifications (PTMs). The impact of PTMs on the HMGB/PtDNA complex at atomistic level is here investigated by enhanced sampling molecular simulations. The PTMs turn out to affect the structure of the complex, the mobility of several regions (including the platinated site), and the nature of the protein/PtDNA non-covalent interactions. Overall, the multisite PTMs increase significantly the apparent synchrony of all the contacts between the protein and PtDNA. Consequently, the hydrophobic anchoring of the side chain of F37 between the two cross-linked guanines at the platinated site-a key element of the complexes formation - is more stable than in the complex without PTM. These differences can account for the experimentally measured greater affinity for PtDNA of the protein isoforms with PTMs. The collective behavior of multisite PTMs, as revealed here by the synchrony of contacts, may have a general significance for the modulation of intermolecular recognitions occurring in vivo.
顺铂是最广泛使用的抗癌药物之一。不幸的是，其效率受到耐药性的严重阻碍。高迁移率族框 (HMGB) 蛋白可以通过特异性结合铂化 DNA (PtDNA) 损伤来使肿瘤细胞对顺铂敏感。在体内，HMGB/PtDNA 结合受多部位翻译后修饰 (PTM) 调控。通过增强采样分子模拟研究了 PTM 对原子水平 HMGB/PtDNA 复合物的影响。结果表明，PTM 会影响复合物的结构、几个区域（包括铂化部位）的流动性以及蛋白质/PtDNA 非共价相互作用的性质。总体而言，多部位 PTM 显著增加了蛋白质和 PtDNA 之间所有接触的表观同步性。因此，F37 侧链在铂化部位两个交联鸟嘌呤之间的疏水性锚定（复合物形成的关键要素）比没有 PTM 的复合物更稳定。这些差异可以解释实验测量的具有 PTM 的蛋白质异构体对 PtDNA 的更大亲和力。这里通过接触的同步性揭示的多部位 PTM 的集体行为可能对体内发生的分子间识别的调节具有普遍意义。
