Computational Insight into the Intercalating Properties of Cryptolepine

DNA is held together by hydrogen bonding between nucleobases (adenine-thymine, guanine-cytosine) and van der Waals interactions between adjacent base pairs’ π orbitals. Intercalating molecules with quasiplanar structures utilize van der Waals interactions to bind between DNA base pairs. Experimental studies have shown that Cryptolepine preferentially intercalates between nonalternating cytosine and guanine base pairs. However, an atomic-scale mechanism that can explain the selective intercalation is still missing. Using molecular dynamics and density functional theory, we demonstrate how Cryptolepine binds to DNA base pairs, rationalizing its selectivity by analyzing the intermolecular bonding strength predicted by Umbrella Sampling and Free Energy Perturbation calculations. Cryptolepine is stable in all DNA base conformations studied, and the binding is a combination of van der Waals interactions with the nucleobases surrounding its π system and hydrogen bonds with the DNA backbone and nucleobases. Our model predicts a preference for cytosine and guanine base pairs with a more prominent preference for alternating cytosine and guanine base pairs. These findings illustrate Cryptolepine’s binding mechanism to DNA and highlight the importance of hydrogen bonds and van der Waals interactions.