Structural dynamics of clinically-reported VUS in the BARD1 ARD-BRCT region to predict the molecular basis of alterations.

The functional domains of BARD1, comprise the Ankyrin Repeat Domain (ARD), C-Terminal domains (BRCTs), and a linker between ARD and the BRCTs, which are known to bind to Cleavage stimulation Factor complex-subunit of 50 kDa (CstF-50). The pathogenic mutation Q564H in the BARD1 ARD-linker-BRCT region has been reported to abrogate the binding between BARD1 and CstF-50. Intermediate penetrance variants of BARD1 are associated with the occurrence of breast cancer. Therefore, seven missense variants of unknown significance (VUS), L447V, P454L, N470S, V507M, I509T, C557S, and Q564H of BARD1, reported in the ARD domain and the linker region were evaluated molecular dynamics (MD) simulations. The mutants revealed statistically significantly different distributions of RMSD (root mean square deviation), residuewise RMSF (root mean square fluctuation), (radius of gyration), SASA (solvent accessible surface area), and COM (centre of mass)-to-COM distance between the ARD and the BRCT repeat, between the wild type and each mutant. The secondary structural composition of the mutants was slightly altered relative to that of the wild type. However, the reported in-silico based prediction require further validation using in-vitro, biophysical and structure-based approachCommunicated by Ramaswamy H. Sarma.