The importance of stereochemistry in the disorder-order continuum of protein-protein interactions

Intrinsically disordered proteins can bind via the formation of highly disordered protein complexes without the formation of 3D-structure. Most naturally occurring proteins are “left-handed” or levorotatory (L), made up only of L-amino acids, imprinting molecular structure and communication with stereochemistry. In contrast, their mirror image “right-handed” or dextrorotatory (D) amino acids are rare in Nature. Whether disordered protein complexes are truly independent of 3D-topology and thus of chiral constraints is not clear. To test the chiral constraints of disordered protein-protein interactions, a set of interacting protein pairs covering the disorder-order continuum was chosen as representative examples. By observing both the natural ligands and their stereochemical mirror images in free and bound states, we discovered that chirality was inconsequential in a fully disordered complex. However, if the interaction relied on the ligand undergoing coupled folding and binding, correct stereochemistry was essential. Between these extremes, binding could be observed for the D-ligand with a strength that correlated with the amount of disorder in the final complex. These findings have important implications for our understanding of protein-protein interactions, the molecular processes leading to complex formation, the use of D-peptides in drug discovery, and the chemistry of protein evolution of the first living entities on Earth.