QSAR studies applied to the prediction of antigen-antibody interaction kinetics as measured by BIACORE.
The objective of this work was to investigate the potential of the quantitative structure-activity relationships (QSAR) approach for predictive modulation of molecular interaction kinetics. A multivariate QSAR approach involving modifications in peptide sequence and buffer composition was recently used in an attempt to predict the kinetics of peptide-antibody interactions as measured by BIACORE. Quantitative buffer-kinetics relationships (QBKR) and quantitative sequence-kinetics relationships (QSKR) models were developed. Their predictive capacity was investigated in this study by comparing predicted and observed kinetic dissociation parameters (k(d)) for new antigenic peptides, or in new buffers. The range of experimentally measured k(d) variations was small (300-fold), limiting the practical value of the approach for this particular interaction. However, the models were validated from a statistical point of view. In QSKR, the leave-one-out cross validation gave Q(2) = 0.71 for 24 peptides (all but one outlier), compared to 0.81 for 17 training peptides. A more precise model (Q(2) = 0.92) could be developed when removing sets of peptides sharing distinctive structural features, suggesting that different peptides use slightly different binding modes. All models share the most important factor and are informative for structure-kinetics relationships. In QBKR, the measured effect on k(d) of individual additives in the buffers was consistent with the effect predicted from multivariate buffers. Our results open new perspectives for the predictive optimization of interaction kinetics, with important implications in pharmacology and biotechnology.
Choulier
Laurence
L
UMR7100-CNRS, ESBS, Bld Sébastien Brandt, 67400 Illkirch Cedex, France and Biacore AB, Rapsgatan 7, SE754 50 Uppsala, Sweden.
Andersson
Karl
K
Hämäläinen
Markku D
MD
van Regenmortel
Marc H V
MH
Malmqvist
Magnus
M
Altschuh
Danièle
D
D000937:Antigen-Antibody Reactions; D015374:Biosensing Techniques; D007140:Immunoglobulin Fab Fragments; D007700:Kinetics; D018448:Models, Immunological; D021281:Quantitative Structure-Activity Relationship
D007140:Immunoglobulin Fab Fragments