title: In silico study of effects of polymorphisms on biophysical chemical properties of oxidized N-terminal domain of X-ray cross-complementing group 1 protein.
abstract: Base excision repair (BER) is the major pathway involved in removal of endogenous and mutagen-induced DNA damage. The X-ray cross-complementing group 1 protein (XRCC1), which participates in BER, is a scaffolding protein. The oxidized XRCC1 N-terminal domain (NTD) forms additional interactions with DNA polymerase β (Pol β). Any change in the residues of a protein (XRCC1, XRCC4, etc.) may alter its stability and function. Many coding regions of genes have single nucleotide polymorphisms (SNPs) that change the conformation of their products, and they are probably involved in some diseases. The R7L and R107H mutations are located in the XRCC1-NTD. In the present study, biophysical chemical properties of oxidized XRCC1-NTD (wild type or mutants) were investigated at different temperatures (290, 295, 298, 301, 304, 309, 310, 311, and 312 K) in water using in silico molecular mechanic computational methods. Comparison of the average calculated potential energies of oxidized XRCC1-NTD reveals that the R7L mutation increases stability, but the R107H and R7L&R107H mutations are destabilizing. Therefore, mutant types of this protein (R107H or R7L&R107H) may not function correctly. Furthermore, quantitative structure-activity relationship (QSAR) of oxidized XRCC1-NTD and docking assay showed that the R7L mutation is advantageous but the R107H and R7L&R107H mutations are disadvantageous for XRCC1-NTD, and in the latter cases it cannot interact with Pol β as well as the wild type does. Hence, DNA repair may be defective. Also, using the equation dE = ∂Ε/(∂Τ)V·dT + ∂Ε/(∂V)T·dV, it was determined that the best temperature for normal activity of oxidized XRCC1-NTD is exactly the natural body temperature (310 K).
authors: Department of Biochemistry, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran. mehrzadjam@yahoo.com.
authors: J
authors: J
authors: Mehrzad
authors: M
authors: M
authors: Monajjemi
authors: M
authors: M
authors: Hashemi
mesh_terms: D019951:DNA Polymerase beta / Q000737:chemistry / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009010:Monte Carlo Method; D010084:Oxidation-Reduction; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D013696:Temperature; D013816:Thermodynamics; D014867:Water / Q000737:chemistry; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; D014867:Water; D019951:DNA Polymerase beta