Structural basis for the sequence-dependent effects of platinum-DNA adducts

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Platinum-based chemotherapy drugs like cisplatin (CP) and oxaliplatin (OX) have varying clinical efficacies.
• Differences are hypothesized to stem from how these drugs bind to DNA and are recognized by cellular proteins.
• Specifically, HMGB1a protein shows higher affinity for CP-DNA adducts compared to OX-DNA adducts.

Purpose of the Study:

• To elucidate the structural basis for differential binding affinities of HMGB1a to CP- and OX-DNA adducts.
• To investigate the role of DNA sequence context in modulating these adduct conformations.
• To understand how drug structure influences DNA-protein interactions in platinum-based chemotherapy.

Main Methods:

• Molecular dynamics simulations were employed to study the conformational dynamics of CP-GG and OX-GG adducts within a specific DNA sequence (TGGA).
• Analysis of hydrogen bond formation patterns between platinum-ammine groups and adjacent DNA bases was used to identify major and minor DNA adduct conformations.
• Computational modeling was used to assess the structural properties favoring protein binding.

Main Results:

• CP-GG and OX-GG adducts exhibit distinct minor conformations, influenced by the surrounding DNA sequence.
• Minor conformations exclusively sampled by CP-GG adducts possess structural features that promote HMGB1a binding.
• The cyclohexane ring of oxaliplatin (OX) restricts DNA conformational flexibility, preventing the sampling of HMGB1a-favored conformations seen with cisplatin (CP).

Conclusions:

• The structural constraints imposed by oxaliplatin's cyclohexane ring alter DNA adduct conformations compared to cisplatin.
• These distinct DNA conformations influence the binding affinities of HMG-domain proteins like HMGB1a.
• DNA sequence context further modulates these conformational preferences, impacting drug-protein interactions and potentially therapeutic outcomes.