Primary vs secondary: Directionalized guest coordination in β-cyclodextrin derivatives

In computational modelling of cyclodextrin (CD) host-guest binding, often only a single binding mode is considered. However, due to the asymmetric feature of CD, the guest can directionally bind to its primary 6′ or secondary 3′ face. Correct modelling of the primary-secondary equilibrium clearly poses a challenge. In this work, we present a comprehensive analysis of fixed-charge modelling of β-CD host-guest complexes. Detailed force field evaluations suggest the reliability of the GAFF2 parameter set, but the electrostatics seem difficult to be accurately reproduced even with the RESP charge scheme. Enhanced sampling simulations are performed to accelerate the translational diffusion of the guest, sample the binding/unbinding events and explore the space of possible binding modes. The error size of predicted binding affinities is intermediate and the predicted primary-secondary preferences agree with experiment for only a fraction of host-guest pairs, which should be attributed to the force field inaccuracy (especially electrostatics).