BCL6の機能に対するnsSNPバリアントの影響を統合計算解析により解読する

BCL6 plays significant roles in various cellular processes and malignancies such as diffuse large B-cell lymphoma. BCL6 performs its functions through binding of its BTB domain to different corepressors. Thus, analyzing the possible structural consequences of nsSNPs on the function of this domain would be imperative. To this end, we have selected the most deleterious SNPs of BCL6 based on various scoring algorithms. Then the selected mutations were modeled, analyzed for various physicochemical and stability properties, and used for molecular docking with the BCoR, NCoR, and SMRT. The obtained complexes were used for the calculation of binding energy and depiction of 2D interaction plots. The docked complexes were also subjected to Molecular Dynamics (MD) simulations to screen their behavior in physiological conditions. The BCL6 SNPs were filtered to 54 nsSNPs of the BTB domain. Using various tools, these nsSNPs were narrowed down to the Q113K, V105G, I78T, and I60T mutations based on their deleteriousness and stability scores. Docking analyses indicated that the exerted mutations mostly reduced the binding affinity, and the MD simulations showed the lower stability of the mutated BCL6 forms during the simulation. Given the attained results, it could be concluded that selected nsSNPs could lead to impaired BCL6 transcriptional repressive function due to loss of stability and binding affinity towards its corepressors. These observations can explain various biological or clinical differences in individuals carrying these SNPs and help with the rational design of novel personalized therapeutics. The results found by computer simulations are suggesting new experiments that need to be done in the future to prove that they are biologically and clinically applicable.