We found that subtle amino acid substitutions reshape DNA recognition:

⚡ DNMT3A uses Arg836 → rigid hydrogen bonding + electrostatic anchoring, favors pyrimidines (C/T).
🤸‍♀️ DNMT3B replaces Arg836 with Lys777 and introduces Asn779 → flexible and cooperative readout with broader substrate tolerance.

To answer this, we ran 16 μs MD sims and built a new framework: Comparative Dynamics Analysis (CDA).

CDA integrates two complementary perspectives:
➡️ Base readout: base-specific hydrogen bonds at major groove
➡️ Shape readout: DNA deformation, electrostatics, and hydrophobic contacts at minor groove