Characterizing the Binding Interactions between DNA-Binding Proteins, XPA and XPE: A Molecular Dynamics Approach.

Abstract

The scaffold nature of Xeroderma pigmentosum complementation group A (XPA) protein makes it an important member of nucleotide excision repair (NER) that removes bulky DNA lesions with the help of various protein–protein interactions (PPI) and DNA–protein interactions. However, many structural insights of XPA’s interaction and the binding patterns with other NER proteins are yet to be understood. Here, we have studied one such crucial PPI of XPA with another NER protein, Xeroderma pigmentosum complementation group A (XPE), by using the previously identified binding site of XPA (residues 185–226) in the Assisted Model Building With Energy Refinement force-field-mediated dynamic system. We studied the relationship between XPA185–226–XPE complex using three different docked models. The major residues observed in all of the models that were responsible for the PPI of this complex were Arg20, Arg47, Asp51, and Leu57 from XPE and the residues Leu191, Gln192, Val193, Trp194, Glu198, Glu202, Glu205, Arg207, Glu209, Gln216, and Phe219 from XPE185–226. During the simulation study, the orientation of XPA was also noted to be changed by almost 180° in models 1 and 3, which remain unchanged in model 2, indicating that XPA interacts with XPE with its N-terminal end facing downward and C-terminal end facing upward. The same was concurrent with the binding of DNA-binding domain region of XPA (aa98–239) with XPE. The N-terminal of XPE was stretched for accommodating XPA. Using the per-residue energy decomposition analysis for the interface residues of all models, the binding affinity between these proteins were found to be dependent on R20, R47, and L57 of XPE and the residues L191, V193, W194, E198, E202, E205, R207, and F219 of XPA. The net binding free energy of the XPA185–226–XPE protein complex was found to be −48.3718 kcal mol–1 for model 1, −49.09 kcal mol–1 for model 2, and −56.51 kcal mol–1 for model 3.