An in silico analysis of the impact of POLE mutations on cladribine docking

Polymerase ε exonuclease (POLE) is an enzyme involved in DNA replication and may be an attractive therapeutic target in various cancers. Here we sought to model the impact of specific POLE mutations on protein function. Due to the lack of a crystal structure, the tertiary structures of the wild type and four common mutants were modeled using I-Tasser server.Molecular docking and dynamic simulation studies were performed, and the structure and function of the mutants analyzed through residue conservation analysis and protein folding energy changes.All mutants of POLE gene had favorable binding affinities compared with their wild type of counterpart. The P286R variant, but not the other variants, disrupted cladribine binding to the protein. Similarly, dynamics studies revealed instability of the P286R mutant, while V411L, L424V, and L424F appeared to favor cladribine binding.Since P286R is a hotspot mutation in endometrioid carcinomas, patients with this variant may not respond to cladribine. Population-based pharmacogenomics studies will be required to validate our results.