Primary vs Secondary: Directionalized Guest Coordination in β-Cyclodextrin Derivatives

The cyclodextrin (CD) and its derivatives as useful drug carriers and reservoirs are widely used in pharmaceutical and chemical industries. The CD-guest (drug) and more generally host-guest coordinations are often considered prototypical cases that are much simpler than biological systems. As a result, in computational modelling even with dynamics propagation, only a single binding pose is considered. However, due to the asymmetric feature of the CD host, the guest can directionally bind to its primary 6’ or secondary 3’ face. Correct modelling of the primary-secondary equilibrium clearly poses a challenge, and any static or dynamic calculations modelling only a single binding preference would introduce systematic biases of unknown magnitude. In this work, using the β-CD host-guest set in a recent grand challenge, we present a comprehensive analysis of various aspects of fixed-charge modelling of β-CD host-guest complexes. The force field parameters (electrostatics and bonded terms) are evaluated in a detailed way, and the best parameter combination is employed in enhanced sampling simulations that accelerate the translational diffusion of the guest molecule, sample the binding/unbinding events extensively, and thus explore the space of possible binding modes. Finally, the binding affinities and the primary-secondary equilibrium (directionalized guest coordination preference) are computed and compared with the experimental reference. Possible reasons for deviations and further ways to improve the quality of calculation are discussed.