Burial Level Change Defines a High Energetic Relevance for Protein Binding Interfaces

Area of Science:

• Structural biology
• Computational biophysics
• Protein-protein interactions

Background:

• Traditional definitions of protein-protein interfaces (e.g., atomic contact, solvent accessibility change) do not accurately capture energetically crucial regions.
• Residue burial depth is linked to atomic energy, suggesting its change upon complexation is relevant to binding.
• Distinguishing burial level change from absolute burial level is critical for accurate interface analysis.

Purpose of the Study:

• To investigate the relationship between changes in residue burial level upon complexation and protein binding.
• To develop a novel definition of protein interfaces based on burial level changes.
• To assess the utility of this new definition for predicting binding hot spots.

Main Methods:

• Hypothesized that interfaces comprise residues with significant burial level changes post-complexation.
• Defined interfaces as onion-like structures based on the extent of burial level change.
• Evaluated the energetic importance of residues within these defined interfaces.

Main Results:

• The newly defined interfaces more accurately encompass energetically important residues.
• Binding free energy distribution within these interfaces follows a progressive pattern from outer layers to the core.
• The proposed approach demonstrates superior or comparable F-measure performance in predicting binding hot spots compared to energy modeling and machine learning methods.

Conclusions:

• Changes in residue burial level upon complexation provide a more precise definition of protein-protein interfaces.
• This burial-centric definition facilitates accurate identification of energetically critical residues and binding hot spots.
• The method offers a computationally efficient and effective alternative for analyzing protein-protein interactions.