ArticlePloS one2015
How structural and physicochemical determinants shape sequence constraints in a functional enzyme.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Multiple molecular and cellular properties jointly affect protein and site-specific evolutionary rates.bioRxiv : the preprint server for biology · 2026Article
- Predicting Metalloprotein Redox Potentials with Machine Learning: A Focus on Iron-Sulfur Systems.Journal of chemical information and modeling · 2025Article
- An augmented transformer model trained on protein family specific variant data leads to improved prediction of variants of uncertain significance.Human genetics · 2025Article
- A look beyond the QR code of SNARE proteins.Protein science : a publication of the Protein Society · 2024Article
- Context-aware geometric deep learning for protein sequence design.Nature communications · 2024Article
- Substitution Models of Protein Evolution with Selection on Enzymatic Activity.Molecular biology and evolution · 2024Article
- Machine Learning for Efficient Prediction of Protein Redox Potential: The Flavoproteins Case.Journal of chemical information and modeling · 2022Article
- Sequence dependencies and biophysical features both govern cleavage of diverse cut-sites by HIV protease.Protein science : a publication of the Protein Society · 2022Article
- Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design.Chemical reviews · 2021Review
- Estimating the Influence of Physicochemical and Biochemical Property Indexes on Selection for Amino Acids Usage in Eukaryotic Cells.Journal of molecular evolution · 2021Article
- Comprehensive Analysis of G1 Cyclin Docking Motif Sequences that Control CDK Regulatory Potency In Vivo.Current biology : CB · 2020Article
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- Building blocks for commodity augmented reality-based molecular visualization and modeling in web browsers.PeerJ. Computer science · 2020Article
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- Identification of non-conserved residues essential for improving the hydrocarbon-producing activity of cyanobacterial aldehyde-deformylating oxygenase.Biotechnology for biofuels · 2019Article
- Structural, physicochemical and dynamic features conserved within the aerolysin pore-forming toxin family.Scientific reports · 2017Article
- Article
- Extensively Parameterized Mutation-Selection Models Reliably Capture Site-Specific Selective Constraint.Molecular biology and evolution · 2016Article
- Molecular Determinants of Mutant Phenotypes, Inferred from Saturation Mutagenesis Data.Molecular biology and evolution · 2016Article
- Molecular Effects of Concentrated Solutes on Protein Hydration, Dynamics, and Electrostatics.Biophysical journal · 2016Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
The need for interfacing structural biology and biophysics to molecular evolution is being increasingly recognized. One part of the big problem is to understand how physics and chemistry shape the sequence space available to functional proteins, while satisfying the needs of biology. Here we present a quantitative, structure-based analysis of a high-resolution map describing the tolerance to all substitutions in all positions of a functional enzyme, namely a TEM lactamase previously studied through deep sequencing of mutants growing in competition experiments with selection against ampicillin. Substitutions are rarely observed within 7 Å of the active site, a stringency that is relaxed slowly and extends up to 15-20 Å, with buried residues being especially sensitive. Substitution patterns in over one third of the residues can be quantitatively modeled by monotonic dependencies on amino acid descriptors and predictions of changes in folding stability. Amino acid volume and steric hindrance shape constraints on the protein core; hydrophobicity and solubility shape constraints on hydrophobic clusters underneath the surface, and on salt bridges and polar networks at the protein surface together with charge and hydrogen bonding capacity. Amino acid solubility, flexibility and conformational descriptors also provide additional constraints at many locations. These findings provide fundamental insights into the chemistry underlying protein evolution and design, by quantitating links between sequence and different protein traits, illuminating subtle and unexpected sequence-trait relationships and pinpointing what traits are sacrificed upon gain-of-function mutation.
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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.