Abstract
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 (ΔG
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 (ΔG
X
>0 kcal/mol) trigger antibodies recognizing full protein but not peptide, and unstable peptides (ΔG
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.
In the current paradigm of immune system recognition, T cell receptors bind to relatively short peptide sequences complexed with major histocompatibility complex proteins on the surface of antigen presenting cells, while B cell receptors recognize unprocessed protein structures. Yet, ample data exist showing that peptide immunization can trigger B cell responses targeting both the immunizing peptide and peptidelike motifs contained within intact protein—despite the fact that the folding stability of such peptides is often quite low. Using thermodynamic modeling and the technique of molecular dynamics simulations, this work provides a cogent framework for understanding the relative capacity of inherently unstable peptide structures to faithfully trigger B cell antibody production against specific conformational motifs found in native/intact proteins.
