A λ-dynamics investigation of insulin Wakayama and other A3 variant binding affinities to the insulin receptor.

This work addresses a decades-old question of how subtle modifications to insulin's A3 side chain affects its binding affinity to the insulin receptor. λ-Dynamics computed free energies of binding match experimental activity trends with high accuracy. Atomistic insights into hormone-receptor protein-protein interactions were obtained through a detailed investigation of λ-dynamic trajectories. This work quantifies the effects of adding and removing atoms to insulin's conserved A3 residue and identifies clear conformational preferences for insulin A3 residues when bound to the insulin receptor.