# Protein folding: the energy landscape

> Why a chain finds its fold: a random search would take forever (Levinthal), but the energy landscape is a funnel with many downhill routes to one native state, the free-energy minimum that the sequence sets (Anfinsen). With the backbone angles of the native state, a free-energy surface and a molecular dynamics box.

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- Open in the LabCanvas editor (LabCanvas account): https://www.labcanvas.com/editor.html?template=protein-folding-energy-landscape
- Updated: 2026-10-14
- Category: Drug discovery & proteins
- Method: Protein folding
- Starting materials: An unfolded polypeptide chain
- Product: The native fold, the free-energy minimum
- Key result: Landscapes, angles and the surface are schematic or synthetic examples
- Figure: 1920 × 1080 px, 49 editable layers (6 generated objects with settings)

## Steps

1. **The sequence decides**: The native structure is set by the amino acid sequence (Anfinsen 1973)
2. **No blind search**: A golf-course landscape has no slope to follow; a funnel has many routes downhill (Dill & Chan 1997)
3. **Traps**: Misfolded intermediates can hold a chain up on the way down
4. **Backbone angles**: Folded residues sit in the helix and sheet regions of the Ramachandran plot (Ramachandran 1963)
5. **Simulation**: Molecular dynamics follows the atoms in a box of water (Karplus & McCammon 2002)

## Strengths

- Explains fast folding without a single pathway
- One picture for folding, misfolding and design

## Limitations

- Real landscapes are high-dimensional; drawings project them onto two or three axes

## Uses

- Teaching
- Folding and misfolding studies
- Simulation figures

## References

1. Anfinsen, “Principles that govern the folding of protein chains”, Science 1973. https://doi.org/10.1126/science.181.4096.223 (primary)
2. Dill & Chan, “From Levinthal to pathways to funnels”, Nat. Struct. Biol. 1997. https://doi.org/10.1038/nsb0197-10 (primary)
3. Ramachandran, Ramakrishnan & Sasisekharan, “Stereochemistry of polypeptide chain configurations”, J. Mol. Biol. 1963. https://doi.org/10.1016/S0022-2836(63)80023-6 (method origin)
4. Karplus & McCammon, “Molecular dynamics simulations of biomolecules”, Nat. Struct. Biol. 2002. https://doi.org/10.1038/nsb0902-646 (further reading)
5. Pauling, Corey & Branson, “The structure of proteins: two hydrogen-bonded helical configurations of the polypeptide chain”, PNAS 1951. https://doi.org/10.1073/pnas.37.4.205 (further reading)

Credit: After Anfinsen, Science 1973 (doi:10.1126/science.181.4096.223), Dill & Chan, Nat. Struct. Biol. 1997 (doi:10.1038/nsb0197-10), Ramachandran et al., J. Mol. Biol. 1963 and Karplus & McCammon, Nat. Struct. Biol. 2002. Landscapes, angles and the free-energy surface are synthetic.

## Questions

**What does the “Protein folding: the energy landscape” template show?** Why a chain finds its fold: a random search would take forever (Levinthal), but the energy landscape is a funnel with many downhill routes to one native state, the free-energy minimum that the sequence sets (Anfinsen). With the backbone angles of the native state, a free-energy surface and a molecular dynamics box.

**What are the steps shown in “Protein folding: the energy landscape”?** 1. The sequence decides: The native structure is set by the amino acid sequence (Anfinsen 1973). 2. No blind search: A golf-course landscape has no slope to follow; a funnel has many routes downhill (Dill & Chan 1997). 3. Traps: Misfolded intermediates can hold a chain up on the way down. 4. Backbone angles: Folded residues sit in the helix and sheet regions of the Ramachandran plot (Ramachandran 1963). 5. Simulation: Molecular dynamics follows the atoms in a box of water (Karplus & McCammon 2002).

**What are the starting materials and the product?** Starting materials: An unfolded polypeptide chain. Product: The native fold, the free-energy minimum.

**Which papers is “Protein folding: the energy landscape” based on?** Anfinsen, “Principles that govern the folding of protein chains”, Science 1973 (doi:10.1126/science.181.4096.223); Dill & Chan, “From Levinthal to pathways to funnels”, Nat. Struct. Biol. 1997 (doi:10.1038/nsb0197-10); Ramachandran, Ramakrishnan & Sasisekharan, “Stereochemistry of polypeptide chain configurations”, J. Mol. Biol. 1963 (doi:10.1016/S0022-2836(63)80023-6); Karplus & McCammon, “Molecular dynamics simulations of biomolecules”, Nat. Struct. Biol. 2002 (doi:10.1038/nsb0902-646); Pauling, Corey & Branson, “The structure of proteins: two hydrogen-bonded helical configurations of the polypeptide chain”, PNAS 1951 (doi:10.1073/pnas.37.4.205).

**Can I edit the “Protein folding: the energy landscape” template?** Yes. Open it in the LabCanvas editor: all 49 layers are editable, including 6 generated objects (structures, plots, equipment) with their own settings. Change the text, colours and layout, then export PNG, TIFF, SVG or PDF.

**Do I need an account to use this template?** Not to view it here. To open and edit it, sign in to LabCanvas or create a free account (the free plan keeps up to 3 designs). Downloading the figure is part of LabCanvas Pro (US$19 a month or US$199 a year).