Improving Atom Type Diversity and Sampling in Co-Solvent Simulations Using λ-Dynamics

Here we present a novel co-solvent MD simulation method based on the lambda-dynamics simulation concept that aims to address a serious issue of current co-solvent simulation approaches, the limited chemical diversity of probe molecules ignoring the chemical context of the pharmacophoric feature represented by a probe. The new concept significantly increases the chemical diversity of functional groups investigated during co-solvent simulations. Application to four different test cases highlights the utility of the new approach to identify binding preferences of different functional groups and to correctly rank ligand series that differ by their substitution patterns.