Hydrophobic folding units derived from dissimilar monomer structures and their interactions

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Protein folding is a fundamental biological process.
• Understanding protein folding pathways is key to deciphering protein function and dysfunction.
• Identifying key structural units involved in early folding events remains a challenge.

Purpose of the Study:

• To design an automated procedure for identifying compact hydrophobic folding units within proteins.
• To evaluate these units based on structural and chemical properties relevant to protein folding.
• To correlate these identified units with observed protein folding kinetics.

Main Methods:

• Developed an automated procedure to segment proteins into hydrophobic folding units.
• Evaluated units using compactness, isolation (based on solvent accessible surface area), hydrophobicity, and segment count.
• Employed a one-dimensional search strategy based on hydrophobic contacts, inspired by Holm and Sander.
• Performed sequence order-independent structural comparisons to create a non-redundant dataset.

Main Results:

• Successfully generated a dataset of hydrophobic folding units from diverse protein structures.
• Demonstrated that the number of identified hydrophobic units correlates with observed two- or three-state protein folding kinetics.
• The generated units capture tertiary non-local interactions, potentially representing nucleation sites.

Conclusions:

• The automated procedure effectively identifies biologically relevant hydrophobic folding units.
• These units provide insights into the initial stages of protein folding and can serve as nucleation sites.
• The dataset is valuable for protein folding mechanism studies, fold recognition, and statistical analysis.