Comparative structural and energetic analysis of WW domain-peptide interactions

Area of Science:

• Protein structure and function
• Molecular interactions
• Computational biology

Background:

• WW domains are crucial protein interaction modules binding to proline-rich motifs.
• Understanding WW domain ligand binding is key to deciphering protein interactions.
• Existing classification schemes for WW domains are primarily ligand-based.

Purpose of the Study:

• To infer determinants of WW domain ligand binding propensities.
• To develop a structure-based classification for WW domains.
• To derive quantitative structure-activity relationships (QSARs) for WW domain-peptide interactions.

Main Methods:

• Comparative modeling of 42 WW domains and peptide complexes.
• Experimental peptide library screens.
• Protein interaction property similarity analysis (PIPSA).
• Comparative molecular field analysis (CoMFA), GRID/GOLPE, and comparative binding energy (COMBINE) analyses.

Main Results:

• 3D models provided insights into peptide orientation within WW domain complexes.
• Electrostatic potential identified as a distinguishing feature, leading to a structure-based classification.
• QSAR models identified specificity-determining residues and a novel feature for arginine-containing peptide recognition.
• Designed peptides showed experimentally verified enhanced binding affinity to the yRSP5-1 WW domain.

Conclusions:

• QSAR models effectively predict and enable rational design for improved WW domain-peptide affinity.
• The developed structure-based classification complements existing ligand-based schemes.
• QSAR models hold potential for predicting specificity in uncharacterized WW domains.