Ensemble-based characterization of unbound and bound states on protein energy landscape
Open accessAbstract
Physicochemical description of numerous cell processes is fundamentally based on the energy landscapes of protein molecules involved. Although the whole energy landscape is difficult to reconstruct, increased attention to particular targets has provided enough structures for mapping functionally important subspaces associated with the unbound and bound protein structures. The subspace mapping produces a discrete representation of the landscape, further called energy spectrum. We compiled and characterized ensembles of bound and unbound conformations of six small proteins and explored their spectra in implicit solvent. First, the analysis of the unbound-to-bound changes points to conformational selection as the binding mechanism for four proteins. Second, results show that bound and unbound spectra often significantly overlap. Moreover, the larger the overlap the smaller the root mean square deviation (RMSD) between the bound and unbound conformational ensembles. Third, the center of the unbound spectrum has a higher energy than the center of the corresponding bound spectrum of the dimeric and multimeric states for most of the proteins. This suggests that the unbound states often have larger entropy than the bound states. Fourth, the exhaustively long minimization, making small intrarotamer adjustments (all-atom RMSD ≤ 0.7 Å), dramatically reduces the distance between the centers of the bound and unbound spectra as well as the spectra extent. It condenses unbound and bound energy levels into a thin layer at the bottom of the energy landscape with the energy spacing that varies between 0.8-4.6 and 3.5-10.5 kcal/mol for the unbound and bound states correspondingly. Finally, the analysis of protein energy fluctuations showed that protein vibrations itself can excite the interstate transitions, including the unbound-to-bound ones.
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Evidence points to the conformational selection binding mechanism, which allows one to precompute the conformational ensemble of the interacting molecule(s) and dock the separate conformers with limited conformational search.
“In a long-standing debate between the proponents of the “induced-fit” and the “conformational selection” binding mechanisms [21–23], the evidence pointing to the latter allows one to precompute the conformational ensemble of the interacting molecule(s) and dock the separate conformers with limited conformational search [24,25].”
From Challenges in protein docking (2020) · cites this paper as [21]
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Protein-Protein Docking: From Interaction to Interactome
Vakser, I. A. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2014.08.033 · Cited by 318 · see citing works
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- Authors
- Ruvinsky, A. M., Kirys, T., Tuzikov, A. V., & Vakser, I. A.
- Affiliations
- University of Kansas (US)
- National Academy of Sciences of Belarus (BY)
- Corresponding author
- Ruvinsky, Anatoly M.
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 2013-04-29
- Volume
- 22
- Issue
- 6
- Pages
- 734-744
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC3690713
- OpenAlex
- W2594681819
- Cited by
- 9
- References
- 62
- Citations by year
- 2025: 1 · 2023: 1 · 2020: 2 · 2019: 1 · 2018: 1 · 2016: 1 · 2015: 1 · 2014: 1
- FWCI
- 0.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Protein Science (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- arXiv (Cornell University) (submittedVersion)
- arXiv (Cornell University)
- Funders
- NIH (R01GM074255)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › Advanced Physical and Chemical Molecular Interactions
- Keywords
- protein energy landscape, conformational ensembles, conformational selection, protein-ligand binding, energy spectrum, implicit solvent, protein vibrations, small proteins
- MeSH terms
- Animals, Humans, Protein Binding, Protein Conformation, Proteins, Thermodynamics
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