Abstract: The invention provides methods of dynamically simulating molecular interactions between a target molecule and a plurality of ligand molecules. The ligand molecules may be presented in the model as a homogeneous set of identical ligands or as a heterogeneous set of different ligands, such as, for example, a set of structural variants of a ligand molecule. Typically, the ligand molecule will be a small organic compound, such as a drug or other small molecule, and the ligand will be a protein or a protein domain, a nucleic acid (i.e., DNA, RNA), or a biomolecular complex of proteins and/or nucleic acid molecules. Unlike all known molecular dynamics simulation methods, the invention provides ligand molecules to the simulation's interaction environment(s) in excess relative to the target molecule.