Computational Binding Studies of Orthogonal Cyclosporin‐Cyclophilin Pairs

A valuable tool for the design of ligands for bioreceptors is provided by the presented combination of Monte Carlo simulations and free energy perturbation calculations. Application of this methodology to an orthogonal receptor–ligand pair based on cyclosporin A and human cyclophilin reproduced the experimentally observed differences in binding affinities and gave detailed insights into the origin of binding preferences with the thermodynamic cycles given on the right. L: reference ligand; P: original protein; bL: bumped ligand; hP: holed protein.