Multiscale Computational Protocols for Accurate Residue Interactions at the Flexible Insulin-Receptor Interface

Area of Science:

• Computational biophysics
• Structural biology
• Biochemistry

Background:

• Accurately quantifying residue contributions in flexible protein-protein interactions is challenging due to experimental structure limitations and inadequate computational tools for noncovalent interactions.
• Existing methods often fail to capture complex nonadditive effects crucial for understanding binding energetics.

Purpose of the Study:

• To develop and validate a hierarchical computational protocol for analyzing flexible protein-protein interactions.
• To quantitatively characterize residue contributions to binding at extensive interfaces.
• To model the specific case of insulin binding to its receptor.

Main Methods:

• Utilized advancements in semiempirical quantum-mechanical (PM6-D3H4S) and implicit solvent (COSMO2) approaches.
• Employed a hierarchical protocol combining molecular dynamics, fragmentation, and virtual glycine scan techniques.
• Validated energetics against DFT-D3 calculations for model dimers.

Main Results:

• The PM6-D3H4S/COSMO2 method successfully described nonadditive effects, outperforming molecular mechanics/generalized Born methods.
• Identified 15 hotspot residues on insulin and 15 on the insulin receptor using the virtual glycine scan.
• Quantified the contributions of these hotspot residues, with identified insulin hotspots aligning with experimental findings.

Conclusions:

• The developed computational strategy provides an accurate and credible tool for quantifying interactions at flexible protein-protein interfaces.
• The modular protocol offers variants for different accuracy and efficiency needs.
• This approach is broadly applicable to various biophysical systems involving protein-protein interactions.