title: Interactions of Multimodal Ligands with Proteins: Insights into Selectivity Using Molecular Dynamics Simulations.
abstract: Fundamental understanding of protein-ligand interactions is important to the development of efficient bioseparations in multimodal chromatography. Here we employ molecular dynamics (MD) simulations to investigate the interactions of three different proteins--ubiquitin, cytochrome C, and α-chymotrypsinogen A, sampling a range of charge from +1e to +9e--with two multimodal chromatographic ligands containing similar chemical moieties--aromatic, carboxyl, and amide--in different structural arrangements. We use a spherical harmonic expansion to analyze ligand and individual moiety density profiles around the proteins. We find that the Capto MMC ligand, which contains an additional aliphatic group, displays stronger interactions than Nuvia CPrime ligand with all three proteins. Studying the ligand densities at the moiety level suggests that hydrophobic interactions play a major role in determining the locations of high ligand densities. Finally, the greater structural flexibility of the Capto MMC ligand compared to that of the Nuvia cPrime ligand allows for stronger structural complementarity and enables stronger hydrophobic interactions. These subtle and not-so-subtle differences in binding affinities and modalities for multimodal ligands can result in significantly different binding behavior towards proteins with important implications for bioprocessing.
authors.affiliation: Howard P. Isermann Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 Eighth Street, Troy, New York 12180, United States.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Parimal
authors.affiliation: Howard P. Isermann Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 Eighth Street, Troy, New York 12180, United States.
authors.forename: Shekhar
authors.initials: S
authors.lastname: Garde
authors.affiliation: Howard P. Isermann Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 Eighth Street, Troy, New York 12180, United States.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Cramer
mesh_terms: D000577:Amides / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D001554:Benzene / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry; D002919:Chymotrypsinogen / Q000737:chemistry*; D045304:Cytochromes c / Q000737:chemistry*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D025801:Ubiquitin / Q000737:chemistry*
chemical_list: D000577:Amides; D000588:Amines; D002264:Carboxylic Acids; D008024:Ligands; D025801:Ubiquitin; D045304:Cytochromes c; D002919:Chymotrypsinogen; D001554:Benzene