Mutual population-shift driven antibody-peptide binding elucidated by molecular dynamics simulations

Abstract

Antibody based bio-molecular drugs are an exciting, new avenue of drug development as an alternative to the more traditional small chemical compounds. However, the binding mechanism and the effect on the conformational ensembles of a therapeutic antibody to its peptide or protein antigen have not yet been well studied. We have utilized dynamic docking and path sampling simulations based on all-atom molecular dynamics to study the binding mechanism between the antibody solanezumab and the peptide amyloid-β (Aβ). Our docking simulations reproduced the experimental structure and gave us representative binding pathways, from which we accurately estimated the binding free energy. Not only do our results show why solanezumab has an explicit preference to bind to the monomeric form of Aβ, but that upon binding, both molecules are stabilized towards a specific conformation, suggesting that their complex formation follows a novel, mutual population-shift model, where upon binding, both molecules impact the dynamics of their reciprocal one.