Molecular Recognition of Platinated DNA from Chromosomal HMGB1.
Molecular Recognition of Platinated DNA from Chromosomal HMGB1.
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DOI：
10.1021/ct500402e
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发表时间：
2014-07
影响因子：
5.5
通讯作者：
T. Nguyen;G. Rossetti;F. Arnesano;E. Ippoliti;G. Natile;P. Carloni
中科院分区：
文献类型：
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作者：
T. Nguyen;G. Rossetti;F. Arnesano;E. Ippoliti;G. Natile;P. Carloni
顺铂以前所未有的效力治疗睾丸癌和卵巢癌。它通过与DNA共价结合来诱导其有益活性。修复酶，从DNA中去除铂损伤，导致耐药性。染色体高迁移率族蛋白（HMGB）可能通过与铂化DNA结合来干扰这一过程。本文采用8 μs多步Walkerwell-tempered元配位模拟方法，研究了HMGB蛋白（HMGB 1A）与含铂寡核苷酸[Pt（NH3）2]（2+）-d（CCUCTCTG*G*ACCTTCC）-d（GGAGAGACCTGGAAGG）（*G为含铂鸟嘌呤）复合物的结构和能量决定簇，并获得了实验结构信息。计算的亲合势与实验符合得很好。这个过程被预测为是由蛋白质驱动的，就像在其他蛋白质/DNA复合物中发现的那样。发现Lys 7残基（其侧链在X射线结构中未解析）与C4 5 '-磷酸相互作用，并且这种相互作用作为分子识别过程的关键方面出现。此外，我们的计算为实验测量的HMGB 1A对铂化DNA的亲和力降低提供了分子基础，这是Cys 22-Cys 44 S-S桥形成的结果（这种氧化不能发生在睾丸中存在的该蛋白质家族的某些成员中，其中药物特别有效）。这种减少很可能是由螺旋H1和H2的小而显著的重排引起的，随后改变了Phe 37并置。
Cisplatin cures testicular and ovarian cancers with unprecedented potency. It induces its beneficial activity by covalently binding to DNA. Repair enzymes, which remove the platinated lesions from DNA, cause drug resistance. Chromosomal High Mobility Group Box proteins (HMGB) may interfere with this process by binding to platinated DNA. Using 8 μs multiple-walker well-tempered metadynamics simulations, here, we investigated the structural and the energetic determinants of one of the HMGB proteins (HMGB1A) in complex with the platinated oligonucleotide [Pt(NH3)2](2+)-d(CCUCTCTG*G*ACCTTCC)-d(GGAGAGACCTGGAAGG) (*G are platinated guanines), for which experimental structural information is available. The calculated affinity is in good agreement with experiment. The process is predicted to be enthalpy-driven, as found for other protein/DNA complexes. The Lys7 residue, whose side-chain was not resolved in the X-ray structure, is found to interact with the C4 5'-phosphate and this interaction emerges as a key facet for the molecular recognition process. In addition, our calculations provide a molecular basis for the experimentally measured decreased affinity of HMGB1A for platinated DNA, as a consequence of Cys22-Cys44 S-S bridge formation (such an oxidation cannot take place in some members of this protein family present in the testis, where the drug is particularly effective). This decrease is likely to be caused by a small yet significant rearrangement of helices H1 and H2 with consequent alteration of the Phe37 juxtaposition.