Thermodynamic stability contributes to immunoglobulin specificity

• Immune repertoires comprise antigen-specific and promiscuous immunoglobulins (Ig).
• Ig promiscuity has been associated with different somatic mutational loads.
• The stability of Ig antigen-binding sites can be reduced by certain somatic mutations.
• The low thermodynamic stability may contribute to the antigen-binding promiscuity of Igs.

Antigen-binding specificity of immunoglobulins is important for their function in immune defense. However, immune repertoires contain a considerable fraction of immunoglobulins with promiscuous binding behavior, the physicochemical basis of which is not well understood. Evolution of immunoglobulin specificity occurs through iterative processes of mutation and selection, referred to as affinity maturation. Recent studies reveal that some somatic mutations could compromise the thermodynamic stability of the variable regions of immunoglobulins. By integrating this observation with the wealth of data on the evolution of novel enzyme activities, we propose that antibody specificity is linked to the thermodynamic stability of the antigen-binding regions, which provides a quantitative distinction between highly specific and promiscuous antibodies.