Point mutations and sequence variability in proteins: Redistributions of preexisting populations
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Here we study the effect of point mutations in proteins on the redistributions of the conformational substates. We show that regardless of the location of a mutation in the protein structure and of its type, the observed movements of the backbone recur largely at the same positions in the structures. Despite the different interactions that are disrupted and formed by the residue substitution, not only are the conformations very similar, but the regions that move are also the same, regardless of their sequential or spatial distance from the mutation. This observation leads us to conclude that, apart from some extreme cases, the details of the interactions are not critically important in determining the protein conformation or in specifying which parts of the protein would be more prone to take on different local conformations in response to changes in the sequence. This finding further illustrates why proteins manifest a robustness toward many mutational events. This nonuniform distribution of the conformer population is consistently observed in a variety of protein structural types. Topology is critically important in determining folding pathways, kinetics, building block cutting, and anatomy trees. Here we show that topology is also very important in determining which regions of the protein structure will respond to sequence changes, regardless of the sequential or spatial location of the mutation.
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The distributions and variability of conformers provide a gradient of binding-site shapes and volumes.
“Depending on the distributions of the conformers and their conformational variability, they provide a gradient of binding site conformations of different shapes and volumes.”
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 [225]
Such binding-site conformational gradients can favorably interact with ensembles of ligands of different sizes.
“These can potentially favorably interact with ensembles of ligands of variable sizes.219,225”
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 [225]
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- Authors
- Sinha, N., & Nussinov, R.
- Affiliations
- Tel Aviv University (IL)
- ORCID
- Nussinov, Ruth
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-03-13
- Volume
- 98
- Issue
- 6
- Pages
- 3139-3144
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC30620
- OpenAlex
- W1968702502
- Cited by
- 110
- References
- 38
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 6 · 2020: 5 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 9 · 2015: 3 · 2014: 5 · 2013: 4 · 2012: 4
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01co056000-057)
- National Cancer Institute (N01 CO 56000)
- 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
- point mutations, backbone mobility, protein topology, sequence-structure relationship, protein folding
- MeSH terms
- Adenylate Kinase, alpha 1-Antitrypsin, Bacterial Proteins, Calmodulin, Humans, Lactoferrin, Muramidase, Myoglobin, Prealbumin, Proteins, Ribonuclease, Pancreatic, Ribonucleases, Genetic Variation, Aspartic Acid Endopeptidases, HIV Protease, Bacteriophage T4, Point Mutation, Protein Structure, Tertiary, Sequence Analysis, Protein
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