Structural and thermodynamic approach to peptide immunogenicity.
In the conventional paradigm of humoral immunity, B cells recognize their cognate antigen target in its native form. However, it is well known that relatively unstable peptides bearing only partial structural resemblance to the native protein can trigger antibodies recognizing higher-order structures found in the native protein. On the basis of sound thermodynamic principles, this work reveals that stability of immunogenic proteinlike motifs is a critical parameter rationalizing the diverse humoral immune responses induced by different linear peptide epitopes. In this paradigm, peptides with a minimal amount of stability (DeltaG(x)<0 kcal/mol) around a proteinlike motif (x) are capable of inducing antibodies with similar affinity for both peptide and native protein, more weakly stable peptides (DeltaG(x)>0 kcal/mol) trigger antibodies recognizing full protein but not peptide, and unstable peptides (DeltaG(x)>8 kcal/mol) fail to generate antibodies against either peptide or protein. Immunization experiments involving peptides derived from the autoantigen histidyl-tRNA synthetase verify that selected peptides with varying relative stabilities predicted by molecular dynamics simulations induce antibody responses consistent with this theory. Collectively, these studies provide insight pertinent to the structural basis of immunogenicity and, at the same time, validate this form of thermodynamic and molecular modeling as an approach to probe the development/evolution of humoral immune responses.
Camacho
Carlos J
CJ
Department of Computational Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. ccamacho@pitt.edu
Katsumata
Yasuhiro
Y
Ascherman
Dana P
DP
D020816:Amino Acid Motifs; D000818:Animals; D000917:Antibody Formation; D000941:Antigens / Q000737:chemistry / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D003198:Computer Simulation; D004797:Enzyme-Linked Immunosorbent Assay; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D006643:Histidine-tRNA Ligase / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
D000941:Antigens; D018985:Epitopes, B-Lymphocyte; D010455:Peptides; D006643:Histidine-tRNA Ligase