Ligand Binding Pathway Elucidation for Cryptophane Host-Guest Complexes

Modeling binding pathways can provide insight into molecular recognition, including kinetic mechanisms, barriers to binding, and gating effects. This work represents a novel computational approach, Hopping Minima, for the determination of conformational transitions of single molecules as well as binding pathways for molecular complexes. The method begins by thoroughly sampling a set of conformational minima for a molecular system. The natural motions of the system are modeled using the normal modes of the sampled minima. The natural motions are utilized to connect conformational minima and are finally combined to form association/binding pathways in the case of molecular complexes. We provide an implementation and example application of the method using alanine dipeptide and a set of chemical host-guest systems: two cryptophane hosts with two guest cations, trimethylammonium and tetramethylammonium. Our results demonstrate that conformational transitions can be modeled and extended to find binding pathways as well as energetic information relevant to the minimum conformations involved. This approach has advantages over simulation-based methods for studying systems with slow binding processes and can help design molecules with preferred binding kinetics.