Cited by 481Protein Structure and DynamicsRNA and protein synthesis mechanismsAdvanced Physical and Chemical Molecular Interactions

F ROM F OLDING T HEORIES TO F OLDING P ROTEINS: A Review and Assessment of Simulation Studies of Protein Folding and Unfolding

Shea, Joan-Emma, Brooks III, Charles L·2001·Annual Review of Physical Chemistry

Abstract

▪ Abstract Beginning with simplified lattice and continuum “minimalist” models and progressing to detailed atomic models, simulation studies have augmented and directed development of the modern landscape perspective of protein folding. In this review we discuss aspects of detailed atomic simulation methods applied to studies of protein folding free energy surfaces, using biased-sampling free energy methods and temperature-induced protein unfolding. We review studies from each on systems of particular experimental interest and assess the strengths and weaknesses of each approach in the context of “exact” results for both free energies and kinetics of a minimalist model for a beta-barrel protein. We illustrate in detail how each approach is implemented and discuss analysis methods that have been developed as components of these studies. We describe key insights into the relationship between protein topology and the folding mechanism emerging from folding free energy surface calculations. We further describe the determination of detailed “pathways” and models of folding transition states that have resulted from unfolding studies. Our assessment of the two methods suggests that both can provide, often complementary, details of folding mechanism and thermodynamics, but this success relies on (a) adequate sampling of diverse conformational regions for the biased-sampling free energy approach and (b) many trajectories at multiple temperatures for unfolding studies. Furthermore, we find that temperature-induced unfolding provides representatives of folding trajectories only when the topology and sequence (energy) provide a relatively funneled landscape and “off-pathway” intermediates do not exist.

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Crossref · 10.1146/annurev.physchem.52.1.499

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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 [57]

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Authors
Shea, J.-E., & Brooks III, C. L.
Affiliations
  • Scripps Research Institute (US)
  • Department of Molecular Biology, TPC6 The Scripps Research Institute La Jolla, California 92037;
Venue
Annual Review of Physical Chemistry
Published
2001-10
Volume
52
Issue
1
Pages
499-535
ISSN
  • 0066-426X (ISSN-L)
  • 1545-1593
OpenAlex
W2147396853
Cited by
481
References
177
Citations by year
2026: 7 · 2025: 5 · 2024: 9 · 2023: 5 · 2022: 6 · 2021: 11 · 2020: 8 · 2019: 7 · 2018: 13 · 2017: 13 · 2016: 16 · 2015: 21 · 2014: 15 · 2013: 21 · 2012: 21
FWCI
2.63
Type
journal article
Language
en
Open access
closed
Locations
  • Annual Review of Physical Chemistry (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute of General Medical Sciences (GM-57513, GM 48807, R01GM057513, R01GM048807)
  • National Center for Research Resources (RR 06009, RR12255, P41RR012255)
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 › Chemistry › Physical and Theoretical Chemistry › Advanced Physical and Chemical Molecular Interactions
Keywords
protein folding, protein unfolding, biased sampling, thermal denaturation, folding kinetics, folding pathways, folding transition state, folding energy landscape, beta-barrel proteins, lattice model, continuum model, atomistic simulation
MeSH terms
Models, Molecular, Protein Folding

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