Coevolutionary dynamics of 53BP1 and its impact on TP53 interaction for DNA damage repair

The p53-binding protein 1 (53BP1) is essential for DNA damage repair via non-homologous end joining (NHEJ) and plays a crucial role in maintaining genomic stability by interacting with the tumor suppressor protein p53, a key regulator of the DNA damage response (DDR). This study investigates the role of coevolution within 53BP1 and its impact on structural integrity and binding affinity with p53. Through multiple sequence alignment and phylogenetic analysis, we identified 72 coevolving groups of amino acid residues, five of which were mapped to the BRCT domain of 53BP1. Mutational effects on these residues were assessed using point mutation mapping and stability analysis via DynaMut, with a detailed evaluation of groups 12 and 16. Docking studies revealed that coevolution-induced modifications enhanced 53BP1-p53 interactions, with group 12 exhibiting the highest binding affinity (-9.9 kcal/mol), followed by group 16 (-9 kcal/mol), both outperforming the wild-type (-8.9 kcal/mol). These modifications resulted in novel interactions that contributed to overall structural stability. Our findings highlight the significance of coevolution in shaping protein-protein interactions and maintaining the structural and functional integrity of 53BP1 protein.