title: Calibrative approaches to protein solubility modeling of a mutant series using physicochemical descriptors.
abstract: A set of physicochemical properties describing a protein of known structure is employed for a calibrative approach to protein solubility. Common hydrodynamic and electrophoretic properties routinely measured in the bio-analytical laboratory such as zeta potential, dipole moment, the second osmotic virial coefficient are first estimated in silico as a function a pH and solution ionic strength starting with the protein crystal structure. The utility of these descriptors in understanding the solubility of a series of ribonuclease Sa mutants is investigated. A simple two parameter model was trained using solubility data of the wild type protein measured at a restricted number of solution pHs. Solubility estimates of the mutants demonstrate that zeta potential and dipole moment may be used to rationalize solubility trends over a wide pH range. Additionally a calibrative model based on the protein's second osmotic virial coefficient, B₂₂ was developed. A modified DVLO type potential along with a simplified representation of the protein allowed for efficient computation of the second viral coefficient. The standard error of prediction for both models was on the order of 0.3 log S units. These results are very encouraging and demonstrate that these models may be trained with a small number of samples and employed extrapolatively for estimating mutant solubilities.
authors.affiliation: Chemical Computing Group Inc., Montreal, QC, Canada. longwf@hotmail.com
authors.forename: William F
authors.initials: WF
authors.lastname: Long
authors.forename: P
authors.initials: P
authors.lastname: Labute
mesh_terms: D019943:Amino Acid Substitution; D055598:Chemical Phenomena; D006863:Hydrogen-Ion Concentration; D007526:Isoelectric Point; D008956:Models, Chemical; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D015202:Protein Engineering; D055550:Protein Stability; D012260:Ribonucleases / Q000737:chemistry / Q000235:genetics; D012995:Solubility; D055672:Static Electricity
chemical_list: D050505:Mutant Proteins; D012260:Ribonucleases; C077002:ribonuclease Sa3