Modeling compact denatured states of proteins

Area of Science:

• Biophysics
• Computational Biology
• Protein Folding

Background:

• Understanding protein folding and denaturation is crucial for molecular biology.
• Compact denatured states of globular proteins remain poorly characterized.
• Experimental techniques like small-angle X-ray scattering provide insights into protein conformations.

Purpose of the Study:

• To propose and model the conformations of compact denatured states in globular proteins.
• To investigate the role of hydrophobic clustering and helical contacts in protein denaturation.
• To compare model predictions with experimental data from small-angle X-ray scattering.

Main Methods:

• Development of a model for protein conformations using three-dimensional cubic lattices.
• Application of the "hydrophobic zippers" method to construct representative ensembles.
• Analysis of radii of gyration, pairwise interatomic distance distributions (P(r)), and Kratky plots.

Main Results:

• Model conformations showed radii of gyration approximately 20% larger than native states.
• Bimodal distributions of P(r) and characteristic Kratky plots were observed, matching experimental data.
• A lattice model of staphylococcal nuclease fragment did not form a single hydrophobic core via zippering, consistent with experimental findings.

Conclusions:

• Compact denatured states are broad ensembles characterized by localized hydrophobic clustering and helical contacts.
• The proposed model successfully reproduces experimental scattering data for protein denaturation.
• The study highlights potential limitations of the hydrophobic zippering mechanism in forming a single core for certain protein fragments.