Free-Energy Simulations of Hydrogen Bonding versus Stacking of Nucleobases on a Graphene Surface

It has been demonstrated by molecular modeling and experiments that free nucleic acid bases form hydrogen-bonded complexes in vacuum but prefer π–π stacking in partially and fully solvated systems. Here we show using molecular dynamics simulations and metadynamics that the addition of a surface (in this case a nanographene monolayer) reverts the situation from stacking back to hydrogen bonding. Watson–Crick as well as several non-Watson–Crick base pairs lying on a graphene surface are significantly more stable in a water environment than a π–π–π-stacked graphene–base–base assembly. It illustrates that the thermodynamics of nucleobase interactions results from a fine balance among hydrogen bonding, stacking, and solvation, and that these effects must be considered in molecular design.