Modeling competitive guest binding to β-cyclodextrin molecular printboards

Anchoring of functionalized guest molecules to self-assembled monolayers (SAMs) is key to the development of molecular printboards for nanopatterning. One very promising system involves guest binding to immobilized beta-cyclodextrin (beta-CD) hosts, with guest: host recognition facilitated by a hydrophobic interaction between uncharged anchor groups on the guest molecule and beta-CD hosts self- assembled at gold surfaces. We use molecular dynamics free energy (MDFE) simulations to describe the specificity of guest: beta-CD association. We find good agreement with experimental thermodynamic measurements for binding enthalpy differences between three commonly used phenyl guests: benzene, toluene, and beta-butylbenzene. van der Waals interaction with the inside of the host cavity accounts for almost all of the net stabilization of the larger phenyl guests in beta-CD. Partial and full methylation of the secondary rim of beta-CD decreases host rigidity and significantly impairs binding of both phenyl and larger adamantane guest molecules. The beta-CD cavity is also very intolerant of guest charging, penalizing the oxidized state of ferrocene by at least 7 kcal/mol. beta-CD hence expresses moderate specificity toward uncharged organic guest molecules by van der Waals recognition, with a much higher specificity calculated for electrostatic recognition of organometallic guests.