title: An orientation sensitive approach in biomolecule interaction quantitative structure-activity relationship modeling and its application in ion-exchange chromatography.
abstract: Quantitative structure-activity relationship (QSAR) modeling for prediction of biomolecule parameters has become an established technique in chromatographic purification process design. Unfortunately available descriptor sets fail to describe the orientation of biomolecules and the effects of ionic strength in the mobile phase on the interaction with the stationary phase. The literature describes several special descriptors used for chromatographic retention modeling, all of these do not describe the screening of electrostatic potential by the mobile phase in use. In this work we introduce two new approaches of descriptor calculations, namely surface patches and plane projection, which capture an oriented binding to charged surfaces and steric hindrance of the interaction with chromatographic ligands with regard to electrostatic potential screening by mobile phase ions. We present the use of the developed descriptor sets for predictive modeling of Langmuir isotherms for proteins at different pH values between pH 5 and 10 and varying ionic strength in the range of 10-100mM. The resulting model has a high correlation of calculated descriptors and experimental results, with a coefficient of determination of 0.82 and a predictive coefficient of determination of 0.92 for unknown molecular structures and conditions. The agreement of calculated molecular interaction orientations with both, experimental results as well as molecular dynamic simulations from literature is shown. The developed descriptors provide the means for improved QSAR models of chromatographic processes, as they reflect the complex interactions of biomolecules with chromatographic phases.
authors.affiliation: Section IV: Biomolecular Separation Engineering, Institute of Engineering in Life Sciences, Karlsruhe Institute of Technology (KIT), Engler-Bunte-Ring 3, 76131 Karlsruhe, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kittelmann
authors.affiliation: Section IV: Biomolecular Separation Engineering, Institute of Engineering in Life Sciences, Karlsruhe Institute of Technology (KIT), Engler-Bunte-Ring 3, 76131 Karlsruhe, Germany.
authors.forename: Katharina M H
authors.initials: KM
authors.lastname: Lang
authors.affiliation: Bioprocess Engineering (BPE), Department of Biotechnology, Delft University of Technology, Julianalaan 67, 2628 BC Delft, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Ottens
authors.affiliation: Section IV: Biomolecular Separation Engineering, Institute of Engineering in Life Sciences, Karlsruhe Institute of Technology (KIT), Engler-Bunte-Ring 3, 76131 Karlsruhe, Germany. Electronic address: Juergen.Hubbuch@kit.edu.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hubbuch
mesh_terms: D002852:Chromatography, Ion Exchange / Q000379:methods*; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009994:Osmolar Concentration; D011506:Proteins / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity
chemical_list: D008024:Ligands; D011506:Proteins
keywords: Binding orientation; Ion-exchange chromatography; Isotherm; Predictive modeling; Quantitative structure–activity relationship (QSAR); Retention modeling