Exploring structures in protein folding funnels with free energy functionals: the denatured ensemble

Area of Science:

• Protein folding thermodynamics
• Biophysical chemistry
• Computational biology

Background:

• Partially folded proteins exhibit complex structures crucial for function.
• Understanding protein folding pathways requires accurate free energy models.
• Existing models often simplify the many-body interactions governing folding.

Purpose of the Study:

• To formulate free energy functionals for describing structure formation in partially folded proteins.
• To incorporate inhomogeneous contact energies, chain entropy, and cooperative forces.
• To interpret experimental data on protein structure occupancy.

Main Methods:

• Development of free energy functionals accounting for inhomogeneous contact energies and cooperative forces.
• Application of minimal frustration principle.
• Interpretation of experimental data including hydrogen protection factors and NMR order parameters.

Main Results:

• The proposed free energy functionals successfully describe structure formation in partially folded proteins.
• The models provide insights into the fractional occupancy of local structures.
• Experimental data from lysozyme and alpha-lactalbumin are interpreted using the developed functionals.

Conclusions:

• The developed free energy functionals offer a robust framework for studying partially folded proteins.
• These functionals are valuable tools for interpreting experimental probes of protein structure.
• The study advances our understanding of the forces driving protein folding and stability.