Sequence-specific recognition of cancer drug-DNA adducts by HMGB1a repair protein.
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.
Department of Chemical and Biological Engineering, University of Colorado, Boulder, Colorado, USA.
Robert M
RM
Elder
Arthi
A
Jayaraman
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D003198:Computer Simulation; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy*; D009690:Nucleic Acid Conformation; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000077150:Oxaliplatin; D011485:Protein Binding; D013816:Thermodynamics; D013941:Thymine / Q000737:chemistry
D000970:Antineoplastic Agents; D018736:DNA Adducts; D004273:DNA, Neoplasm; D024243:HMGB1 Protein; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin; D013941:Thymine