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The chromatography can provide high selectivity to meet high purity required for biopharmaceuticals products.However,till now the understanding on the microscopic mechanism (molecular interactions) of the chromatography is quite limited,which certainly hinder the optimization of separation conditions and the development of novel technologies.With the mixed-mode chromatography (MMC) for antibody purification as the model,the methods of molecular simulation was introduced to study the molecular interactions and separation mechanism during the bioprocess.MMC is a novel technology for bioproduct separation,especially for antibody.The mixed-mode ligands typically combine multiple binding modes,such as hydrophobic interaction,electrostatic forces and hydrogen bonding,resulting in a variety of protein-ligand interactions and unique selectivity.To better understand the ligand-protein interactions during the separation,a molecular simulation approach has been established with the methods of molecular docking and dynamic simulation.The results indicate that at neutral conditions the ligand can bind stably on some special hydrophobic pockets on the IgG surface.When the pH lowers to 4.0,the ligand would depart quickly from the protein surface due to the charge-induced electrostatic repulsion.The effects of ligand structure,ligand cluster,gel matrix and liquid conditions on the ligand-protein interactions can also be investigated with the methods of molecular simulation,and the binding energies could be evaluated.The molecular simulation results would be useful for the process development and the design of novel ligands.With the computer-aided molecular simulations approaches,it is possible to evaluate the multiple interactions between target protein and functional ligand at molecular detail,which certainly help to explore the molecular mechanism of bioseparation,optimize the separation conditions and develop new ligands for bio-product recovery and purification.