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Fig. 3 | Orphanet Journal of Rare Diseases

Fig. 3

From: Molecular mechanics and dynamic simulations of well-known Kabuki syndrome-associated KDM6A variants reveal putative mechanisms of dysfunction

Fig. 3

Representative impact analyses. a A heatmap representation of the global pKa shifts due to each mutation. pKa shifts of the residues that are directly affected by the substitution (e.g., H1060 of the H1060L mutant or H1146A, E1148A, R1255W, and R1351Q original residues and newly introduced charged residues such as C1135R, Q1212R, and Q1248R) are not shown and only indirect effects are represented. Shift amounts in pH unit are color-coded (indicator bar on right). The vertical axis shows the list of titratable residues in a descending order from the top. Noticeably affected residues are indicated on both sides; key functional residues on left and potential allosteric residues on right. b, c MD-based evaluation of global dynamic alterations, such as b the comparison of RMSD distribution and median values and c the absolute average RMSF differences. Wild type (blue), benign (green), damaging controls (red) and Kabuki variants (orange) are shown. Various comparative values have been tested and ‘Median Difference’ for RMSD and Avg. (|WT-variant|)’ per residue were chosen as the best metrics and plotted for variant impact assessment. All Kabuki variants displayed elevated global motions that deviate from the wild type

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