Computational analysis of non-synonymous SNPs-induced structural perturbations and histone binding alterations in the...

PWWP2A and PWWP2B are chromatin-binding proteins that play a significant role by recognizing methylated histone tails, H3K36me3. Their genetic variants are less characterized when compared to other chromatin-binding proteins. Out of the 1123 and 1300 SNPs reported for the PWWP2A and PWWP2B in Ensemble and dbSNP databases, 13 nsSNPs in the PWWP domain of PWWP2A and 8 in PWWP2B were prioritized for investigation. It was observed that most of these residues are in a buried region of the PWWP domain, and any substitution might result in the loss of interactions in the hydrophobic core and compromise overall domain integrity. Additionally, the gained hydrogen bonds were found to be unlikely in compensating the native interactions; instead, they act as stabilizing ones. Docking and structural analyses further demonstrated that substitutions within the aromatic cage and its peripheral loop regions predominantly destabilize the PWWP fold and remodel the interaction interface, providing a mechanistic explanation for impaired chromatin recognition. Such structural perturbations are likely to alter the electrostatic and hydrophobic properties of the binding surface, thereby weakening histone mark recognition and reducing chromatin-binding efficiency. Especially variants such as W695R and T700A in PWWP2A, and T536M and D492G/H in PWWP2B, appear to be potential candidates for further investigation because these substitutions consistently showed distinct structural deviations across multiple analyses. Considering the detrimental effects of these nsSNPs, this study prioritizes them for experimental validation to confirm their role in disease, as they have a high likelihood to disrupt PWWP domain-mediated interactions and reduce chromatin-binding efficiency.