Lessons about Protein Folding and Binding from Archetypal Folds

Area of Science:

• Protein biophysics and structural biology
• Investigating the fundamental physical chemistry governing protein structure and function.

Background:

• Protein function depends on complex 3D structures, selective binding, and conformational changes.
• Decades of research have struggled to fully predict and understand protein folding mechanisms from amino acid sequences.
• Previous studies on single-domain proteins suggested simple, all-or-none folding kinetics, limiting mechanistic understanding and simulation accuracy.

Purpose of the Study:

• To analyze the kinetics, thermodynamics, mechanisms, and functions of archetypal protein folds.
• To establish archetypal folds as benchmarks for atomistic simulations of protein dynamics.
• To explore the connections between archetypal folds, intrinsically disordered proteins, and conformational rheostats.

Main Methods:

• Ultrafast kinetic methods to measure elementary protein folding/unfolding motions.
• Differential scanning calorimetry, multiprobe, and NMR to analyze thermodynamic transitions.
• Single-molecule analyses and computational approaches to explore biological and technological roles.

Main Results:

• Archetypal folds exhibit folding/unfolding rates that set pre-exponential factors for conformational transitions (~1 μs).
• Developed methods reveal gradual, minimally cooperative unfolding transitions in archetypal folds.
• Unexpected links found between archetypal folds and the folding of intrinsically disordered proteins.

Conclusions:

• Archetypal folds serve as crucial models for understanding protein folding kinetics and thermodynamics.
• The study of archetypal folds opens new avenues for protein science and reveals potential roles as conformational rheostats.
• Findings provide benchmarks for atomistic simulations and insights into intrinsically disordered protein behavior.