Quantitative characterization of protein-protein binding across extensive flexible interfaces is a daunting task because of the and the lack of computational tools for reliable evaluation of all the types of non-covalent interactions. Herein, we capitalize on the recent developments in semiempirical quantum mechanical (SQM) methods and present a hierarchical computational protocol which entails molecular dynamics (MD), fragmentation and virtual glycine scan calculations and apply it to insulin/insulin receptor (IR) binding which had been thoroughly studied both, biochemical and recently also structurally by use of cryo-EM. Comparison of SQM and molecular mechanical (MM) interaction energies to reference DFT-D3 calculations showed a perfect agreement for small dimers with the exception of S…O contacts for which MM failed. For efficient identification of interaction “hotspots”, the use of SQM interaction energies on MM optimized snapshots from MD exhibited an excellent agreement with the experimental data. The developed protocol is general and can thus be used for quantification of interactions across other flexible protein-protein interfaces.