Folding funnels and binding mechanisms

Ma, Buyong; Kumar, Sandeep; Tsai, Chung-Jung; Nussinov, Ruth

doi:10.1093/protein/12.9.713

Cited by 596Protein Structure and DynamicsProtein Interaction Studies and Fluorescence AnalysisEnzyme Structure and Function

Folding funnels and binding mechanisms

Ma, Buyong, Kumar, Sandeep, Tsai, Chung-Jung, Nussinov, Ruth·1999·Protein Engineering, Design and Selection

DOI 10.1093/protein/12.9.713

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Abstract

The long-held views on lock-and-key versus induced fit in binding arose from the notion that a protein exists in a single, most stable conformation, dictated by its sequence. However, in solution proteins exist in a range of conformations, which may be described by statistical mechanical laws and their populations follow statistical distributions. Upon binding, the equilibrium will shift in favor of the bound conformation from the ensemble of conformations around the bottom of the folding funnel. Hence here we extend the implications and the usefulness of the folding funnel concept to explain fundamental binding mechanisms.

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The conformational selection and population shift model provides a more realistic description of molecular mechanism considering ensemble nature.
“The ‘conformational selection and population shift’ model87–89,134 provides a more realistic description of the molecular mechanism considering the ensemble nature of protein molecules.”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [87]
During binding, higher energy (lower population) conformers most complementary to pre-existing ligand conformations can be selected, shifting equilibrium toward them.
“During binding, higher energy (lower population) conformers which are most complementary to some pre-existing ligand conformations can be selected and the equilibrium shifts toward these conformers.87–89,134”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [87]
Biomolecules are dynamical objects that are always interconverting between structures with varying energies, and this is the origin of allosteric mechanisms.
“biomolecules are dynamical objects that are always interconverting between a variety of structures with varying energies,166 and that this is the origin of allosteric mechanisms.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [168]
The conformational selection mechanism theorizes that the energy surface hosts a very large number of conformations, the best-fitting one is selected, with subsequent minor induced fit optimization largely by side chains.
“In contrast, the conformational selection mechanism167−169,185 theorizes that the energy surface hosts a very large number of conformations, and the one that fits best is selected, with subsequent minor induced fit optimization, largely by side chains.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [168]

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Authors: Ma, B., Kumar, S., Tsai, C.-J., & Nussinov, R.
Affiliations: National Institutes of Health (US)
National Cancer Institute (US)
ORCID: Ma, Buyong
Kumar, Sandeep
Tsai, Chung-Jung
Nussinov, Ruth
Venue: Protein Engineering, Design and Selection
Publisher: Oxford University Press (OUP)
Published: 1999-09
Volume: 12
Issue: 9
Pages: 713-720
ISSN: 0269-2139 (ISSN-L)
1741-0134
1741-0126
DOI: 10.1093/protein/12.9.713
OpenAlex: W2123529526
Cited by: 594
References: 75
Citations by year: 2026: 12 · 2025: 15 · 2024: 16 · 2023: 27 · 2022: 21 · 2021: 30 · 2020: 29 · 2019: 27 · 2018: 21 · 2017: 35 · 2016: 33 · 2015: 19 · 2014: 34 · 2013: 43 · 2012: 26
FWCI: 0.70
Type: journal article
Language: en
Open access: closed
Locations: Protein Engineering Design and Selection (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Health and Human Services
Israel Science Foundation
Tel Aviv University
National Institutes of Health (n01co056000-057, NO1-CO-56000, CO-56000)
National Cancer Institute (N01 CO 56000, NO1CO56000)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords: folding funnel, protein binding mechanism, induced fit, lock-and-key model, protein conformational ensembles, conformational statistics, binding equilibrium, protein folding
MeSH terms: Peptides, Protein Binding, Protein Conformation, Proteins, Protein Folding

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