High temperature annealed molecular dynamics simulations as a tool for conformational sampling. Application to the bicyclic “222” cryptand

We have performed “High Temperature Annealed Molecular Dynamics Simulations” (HTAMDS) on the bicyclic 222 cryptand, and on model M+/222 cryptates with different representations of M+. The analysis of four sets of 500 structures allows assessment of the ability of HTAMDS to: (1) interconvert experimentally known conformers starting from one of them, (2) locate the energy minima, (3) generate new conformers of low energy, and (4) account for the average structure observed on the NMR time scale. In view of the ionophoric behavior of 222, structures are also analyzed in terms of the “in/out” orientation of the binding sites. It is found that simulations on the free molecule, although widely sampling the conformational space, do not give structures adequate for cation inclusion. They generate however the lowest energy structure known experimentally and other new closely related ones. Inclusion of the substrate in the simulation (either as a purely electrostatic “driver,” or as a charged sphere) is required to generate conformations found in several complexes. These results suggest that in the field of drug design, conformation of drugs suitable for binding to a given receptor may not be found when the simulations are performed on the isolated drug or substrate.