ArticleProceedings of the National Academy of Sciences of the United States of America2013
Interplay of physics and evolution in the likely origin of protein biochemical function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 62 citations in OpenAlex.
- GlueFinder: A Data-Driven Framework for the Rational Discovery of Molecular Glues.Journal of chemical information and modeling · 2026Article
- Deciphering DEL pocket patterns through contrastive learning.Nature communications · 2026Article
- Entabolons: How Metabolites Modify the Biochemical Function of Proteins and Cause the Correlated Behavior of Proteins in Pathways.Journal of chemical information and modeling · 2025Review
- Accurate prediction by AlphaFold2 for ligand binding in a reductive dehalogenase and implications for PFAS (per- and polyfluoroalkyl substance) biodegradation.Scientific reports · 2023Article
- Implications of the Essential Role of Small Molecule Ligand Binding Pockets in Protein-Protein Interactions.The journal of physical chemistry. B · 2022Article
- De novo protein fold families expand the designable ligand binding site space.PLoS computational biology · 2021Article
- FRAGSITE: A Fragment-Based Approach for Virtual Ligand Screening.Journal of chemical information and modeling · 2021Article
- On the emergence of homochirality and life itself.The biochemist · 2021Article
- DESTINI: A deep-learning approach to contact-driven protein structure prediction.Scientific reports · 2019Article
- Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs.Medicinal research reviews · 2019Review
- Structure and Protein Interaction-Based Gene Ontology Annotations Reveal Likely Functions of Uncharacterized Proteins on Human Chromosome 17.Journal of proteome research · 2018Article
- Complex evolutionary footprints revealed in an analysis of reused protein segments of diverse lengths.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Rational Design of Novel Allosteric Dihydrofolate Reductase Inhibitors Showing Antibacterial Effects on Drug-Resistant Escherichia coli Escape Variants.ACS chemical biology · 2017Article
- On the importance of composite protein multiple ligand interactions in protein pockets.Journal of computational chemistry · 2017Article
- The natural productome.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Why Is There a Glass Ceiling for Threading Based Protein Structure Prediction Methods?The journal of physical chemistry. B · 2017Article
- Catalytic and substrate promiscuity: distinct multiple chemistries catalysed by the phosphatase domain of receptor protein tyrosine phosphatase.The Biochemical journal · 2016Article
- How special is the biochemical function of native proteins?F1000Research · 2016Review
- Are protein-protein interfaces special regions on a protein's surface?The Journal of chemical physics · 2015Article
- Nonlinearities in protein space limit the utility of informatics in protein biophysics.Proteins · 2015Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The intrinsic ability of protein structures to exhibit the geometric and sequence properties required for ligand binding without evolutionary selection is shown by the coincidence of the properties of pockets in native, single domain proteins with those in computationally generated, compact homopolypeptide, artificial (ART) structures. The library of native pockets is covered by a remarkably small number of representative pockets (∼400), with virtually every native pocket having a statistically significant match in the ART library, suggesting that the library is complete. When sequences are selected for ART structures based on fold stability, pocket sequence conservation is coincident to native. The fact that structurally and sequentially similar pockets occur across fold classes combined with the small number of representative pockets in native proteins implies that promiscuous interactions are inherent to proteins. Based on comparison of PDB (real, single domain protein structures found in the Protein Data Bank) and ART structures and pockets, the widespread assumption that the co-occurrence of global structure, pocket similarity, and amino acid conservation demands an evolutionary relationship between proteins is shown to significantly underestimate the random background probability. Indeed, many features of biochemical function arise from the physical properties of proteins that evolution likely fine-tunes to achieve specificity. Finally, our study suggests that a repertoire of thermodynamically (marginally) stable proteins could engage in many of the biochemical reactions needed for living systems without selection for function, a conclusion with significant implications for the origin of life.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.