The Protein-Folding Problem, 50 Years On
Abstract
Protein Folding: Past and Future: Fifty years ago the Nobel Prize in chemistry was awarded to Max Perutz and John Kendrew for determining the structure of globular proteins. Since first viewing their structure of myoglobin, scientists have sought to understand protein folding. Dill and MacCallum (p. 1042 ) review the progress that has been made on three central questions: What is the code that relates sequence to structure? How do proteins fold so fast? Can protein structure be computationally predicted? While we have come some way toward answering these questions, new questions have been gene rated. It is no longer useful to talk about “solving the protein-folding problem”—protein folding has grown into a field of research where the next 50 years promise to be as exciting as the last.
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AlphaFold does not resolve the protein folding problem and does not identify folding pathways.
“AlphaFold does not resolve the decades-long protein folding challenge, nor does it identify the folding pathways.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [52]
According to the funnel hypothesis of protein folding, the native structure of a protein is believed to be the global minimum of its free energy, although many counterexamples exist.
“According to the funnel hypothesis of protein folding, the native structure of a protein is believed to the global minimum of its free energy [177,193], although many counterexamples exist.”
From The prospects of quantum computing in computational molecular biology (2021) · cites this paper as [177]
The argument that a protein must have a specific folding pathway because conformational space is too large is fallacious, since free energy falls progressively as the protein folds, providing sufficient guidance.
“In fact, as has often been pointed out (for example43) this is a fallacious argument, since the free energy falls progressively as the protein folds, providing sufficient guidance44.”
From Critical assessment of methods of protein structure prediction (CASP)—Round <scp>XIV</scp> (2021) · cites this paper as [44]
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- Authors
- Dill, K. A., & MacCallum, J. L.
- Affiliations
- Stony Brook University (US)
- Corresponding author
- Dill, Ken A.
- Venue
- Science
- Published
- 2012-11-23
- Volume
- 338
- Issue
- 6110
- Pages
- 1042-1046
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2014050554
- Cited by
- 1,699
- References
- 72
- Citations by year
- 2026: 140 · 2025: 132 · 2024: 117 · 2023: 148 · 2022: 114 · 2021: 137 · 2020: 123 · 2019: 144 · 2018: 111 · 2017: 123 · 2016: 121 · 2015: 119 · 2014: 94 · 2013: 73 · 2012: 1
- FWCI
- 8.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM34993, R01GM034993)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- protein folding, folding kinetics, folding funnel, energy landscape, thermal fluctuations, protein structure prediction, Protein Data Bank
- MeSH terms
- Amino Acid Sequence, Computer Simulation, Pharmaceutical Preparations, Models, Chemical, Protein Conformation, Proteins, Protein Folding, Caspase 9
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