The Xeroderma pigmentosum complementation group A (XPA) protein functions as a primary damage verifier and as a scaffold protein in nucleotide excision repair (NER) in all higher organisms. New evidence of XPA's existence as a dimer and the redefinition of its DNA-binding domain (DBD) raises new questions regarding the stability and functional position of XPA in NER. Here, we have investigated XPA's dimeric status with respect to its previously defined DBD (XPA98-219) as well as with its redefined DBD (XPA98-239). We studied the stability of XPA98-210 and XPA98-239 homo-dimer systems using all-atom molecular dynamics simulation, and we have also characterized the protein-protein interactions (PPI) of these two homo-dimeric forms of XPA. After conducting the root mean square deviation (RMSD) analyses, it was observed that the XPA98-239 homo-dimer has better stability than XPA98-210. It was also found that XPA98-239 has a larger number of hydrogen bonds, salt bridges, and hydrophobic interactions than the XPA98-210 homo-dimer. We further found that Lys, Glu, Gln, Asn, and Arg residues shared the major contribution toward the intermolecular interactions in XPA homo-dimers. The binding free energy (BFE) analysis, which used the molecular mechanics Poisson-Boltzmann method (MM-PBSA) and the generalized Born and surface area continuum solvation model (GBSA) for both XPA homo-dimers, also substantiated the positive result in favor of the stability of the XPA98-239 homo-dimer. Communicated by Ramaswamy H. Sarma.
Binding Sites DNA, Bacterial