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Updated: Jul 19, 2026
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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
Published on: July 25, 2013
A backbone-based theory of protein folding
George D Rose1, Patrick J Fleming, Jayanth R Banavar
1T. C. Jenkins Department of Biophysics,The Johns Hopkins University, Jenkins Hall, 3400 North Charles Street, Baltimore, MD 21218, USA. grose@jhu.edu
Summary
Protein folding, a spontaneous disorder-order transition, is fundamental to biochemistry. This work proposes a new model where backbone hydrogen bonds, not side-chain interactions, drive protein self-assembly into native structures.
Area of Science:
- Biochemistry
- Structural Biology
- Biophysics
Background:
- Proteins transition from flexible unfolded states to specific 3D structures via folding.
- Current understanding relies on thermodynamics and structural data (X-ray crystallography, NMR spectroscopy).
- Anfinsen's principle states amino acid sequence dictates protein structure, but the self-assembly mechanism is unknown.
Purpose of the Study:
- To review established protein folding concepts.
- To propose an alternative model for protein self-assembly.
- To challenge the prevailing side-chain interaction paradigm.
Main Methods:
- Review of historical and current protein folding theories.
- Proposal of a new model based on backbone hydrogen bond energetics.
- Analysis of protein structural elements (alpha-helices, beta-sheets).
Main Results:
- Established view: Side-chain interactions drive protein folding.
- Proposed model: Backbone hydrogen bonds dominate folding, with preorganization.
- The final fold is selected from a repertoire of hydrogen-bonded structural arrangements.
Conclusions:
- The fundamental mechanism of protein self-assembly remains a key biochemical question.
- A new perspective emphasizes backbone hydrogen bond energetics in protein folding.
- This model suggests a selection process from predefined structural possibilities.
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