Redesigning an antibody fragment for faster association with its antigen.
Traditional approaches for increasing the affinity of protein-protein complexes focus on constructing highly complementary binding surfaces. Recent theoretical simulations and experimental results suggest that electrostatic steering forces can also be manipulated to increase association rates while leaving dissociation rates unchanged, thus increasing affinity. Here we demonstrate that electrostatic attraction can be enhanced between an antibody fragment and its cognate antigen through application of a few simple rules to identify potential on-rate amplification sites that lie at the periphery of the antigen-antibody interface.
Marvin
Jonathan S
JS
Genentech, Inc., Department of Protein Engineering, South San Francisco, California 94080, USA.
Lowman
Henry B
HB
D019943:Amino Acid Substitution; D000915:Antibody Affinity; D000936:Antigen-Antibody Complex / Q000032:analysis; D000937:Antigen-Antibody Reactions; D000941:Antigens / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D003198:Computer Simulation; D015195:Drug Design; D016228:Endothelial Growth Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008222:Lymphokines / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009994:Osmolar Concentration; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D055672:Static Electricity; D013816:Thermodynamics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000936:Antigen-Antibody Complex; D000941:Antigens; D016228:Endothelial Growth Factors; D007128:Immunoglobulin Fragments; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors