Determinants of Protein Folding Pathways: Lessons from Metamorphic Proteins

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• The protein folding problem involves predicting structure from sequence and understanding folding mechanisms.
• Artificial intelligence has advanced structure prediction, but folding mechanisms remain elusive.
• Early studies focused on two-state folding and conserved mechanisms within protein families.

Purpose of the Study:

• To review the evolution of protein folding studies.
• To propose a unified view of protein folding mechanisms.
• To highlight the role of the denatured state in determining folding pathways and topology.

Main Methods:

• Review of existing literature on protein folding.
• Analysis of studies on metamorphic proteins.
• Synthesis of findings to propose a new theoretical framework.

Main Results:

• Metamorphic proteins reveal diverse folding mechanisms from similar sequences.
• Folding pathways are determined at very early stages.
• The denatured ensemble contains biases dictating folding outcomes.

Conclusions:

• Folding mechanisms are selected early in the folding process.
• The denatured state plays a crucial role in defining both folding pathways and the final protein topology.
• A unified view emphasizes the denatured ensemble's central role in protein folding.