Structural insight into inhibition of REV7 protein interaction revealed by docking, molecular dynamics and MM/PBSA studies

In mammalian cells, DNA polymerase xi (Pol xi) catalyzes the TLS step of ICLR. By acting simultaneously with Y-family DNA polymerase, Pol xi completes replication of damaged DNA without removing the damage by inserting a nucleotide opposite the lesion. It has been demonstrated that Pol xi represents a promising target for the treatment of chemotherapy-resistant tumors. The first series of small-molecule inhibitors targeting REV7/REV3L interaction have been identified recently, however, their corresponding binding mechanism is not known. Herein, we performed docking, molecular dynamics and MM/PBSA free energy calculations to study the binding mechanism of REV7 and its inhibitors. It was demonstrated that inhibitors bind to the two pockets divided by the 'safety-belt' structure of REV7, which was supported by the MD simulation. In addition, 2-methylfuran is an important group with an appropriate size to form the stable complex, and hydrophobic contacts were mainly responsible for stable complex formation as revealed by free energy calculation.