Abstract
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.