Exploring the Effect of Preorganization on Binding Affinity in Cyclized Peptidomimetics

Abstract

Peptidomimetics are a class of molecules able to bind and disrupt protein-protein interactions (PPIs) by mimicking complementary structure of a protein binder, making them potential candi-dates for drug molecules. Cyclization is a common strategy intended to increase the binding affinity of peptidomimetics and therefore produce better drug molecules. A simple conformational selection model predicts that increased preorganization leads to increased binding affinity. To explore this idea, we constructed all-atom molecular topologies and performed molecular dynamics simulations of cyclized peptidomimetics to test if their relative preorganization shows a correlation to binding affinity. Our simulations of stapled peptide binders of PUMA suggest this indeed is the case, at least for peptide staples which do not interfere with the binding interface. If further all-atom studies show similar trends, we may conclude that peptide preorganization is an efficient way to screen potential drug molecules, circumventing the computational expense of receptor-ligand dissociation studies.