Intramolecular H-Bonds Govern the Recognition of a Flexible Peptide by an Antibody

Abstract

Molecular recognition is a fundamental event at the core of essentially every biological process. In particular, intermolecular H-bonds have been recognized as key stabilizing forces in antibody-antigen interactions resulting in exquisite specificity and high affinity. Although equally abundant, the role of intramolecular H-bonds is far less clear, and not universally acknowledged. Herein we have carried out a molecular-level study to dissect the contribution of intramolecular H-bonds in a flexible peptide for the recognition by an antibody. We show that intramolecular H-bonds may have a profound, multifaceted, and deleterious effect on the binding affinity by up to 2 kcal mol-1 of free energy. Collectively, our results suggest that antibodies are fine-tuned to recognize transiently stabilized structures of flexible peptides in solution, for which intramolecular H-bonds play a key role. Our results have implications for the design of more efficient vaccines employing short peptides.