ArticleChemical science2021
Temperature artifacts in protein structures bias ligand-binding predictions.
Article in Chemical science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Putrescine-bound structure and multi-temperature crystallography provide new insights into ligand binding and conformational heterogeneity in spermidine synthase.Structural dynamics (Melville, N.Y.) · 2026Article
- DT-TRAP enables accurate target recognition via simplified dosing and low-temperature incubation.Journal of pharmaceutical analysis · 2026Article
- Structural basis for substrate-dependent allostery in oxygen activation by a cytochrome P450 enzyme revealed by analysis at different temperatures.Chemical science · 2026Article
- Unfreezing structural biology for drug discovery.Nature chemical biology · 2026Review
- Some Like It Hot -Structural Changes in Extremophile Rubredoxin at 120 °C.Angewandte Chemie (International ed. in English) · 2026Article
- Multi-Temperature Crystallography of S-Adenosylmethionine Decarboxylase Observes Dynamic Loop Motions.Biomolecules · 2025Article
- Evolution of macromolecular crystallography beamlines at the Swiss Light Source and SwissFEL.Journal of synchrotron radiation · 2025Article
- Probing the modulation of enzyme kinetics by multi-temperature, time-resolved serial crystallography.Nature communications · 2025Article
- Structure-Based Experimental Datasets for Benchmarking Protein Simulation Force Fields [Article v1.0].Living journal of computational molecular science · 2025Article
- Article
- Kinetics-Based State Definitions for Discrete Binding Conformations of T4 L99A in MD via Markov State Modeling.Journal of chemical information and modeling · 2024Article
- A structural perspective on the temperature-dependent activity of enzymes.bioRxiv : the preprint server for biology · 2024Article
- An expanded trove of fragment-bound structures for the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data.Structure (London, England : 1993) · 2024Article
- PopShift: A Thermodynamically Sound Approach to Estimate Binding Free Energies by Accounting for Ligand-Induced Population Shifts from a Ligand-Free Markov State Model.Journal of chemical theory and computation · 2024Article
- Pushed to extremes: distinct effects of high temperature versus pressure on the structure of STEP.Communications biology · 2024Article
- An expanded view of ligandability in the allosteric enzyme PTP1B from computational reanalysis of large-scale crystallographic data.bioRxiv : the preprint server for biology · 2024Article
- Article
- Zirconium Coordination Chemistry and Its Role in Optimizing Hydroxymate Chelation: Insights from Molecular Dynamics.ACS omega · 2023Article
- Pushed to extremes: distinct effects of high temperature vs. pressure on the structure of an atypical phosphatase.bioRxiv : the preprint server for biology · 2023Article
- Pan-HSP90 ligand binding reveals isoform-specific differences in plasticity and water networks.Protein science : a publication of the Protein Society · 2023Article
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Authors and funding
6 authors.
Funding
Abstract
X-ray crystallography is the gold standard to resolve conformational ensembles that are significant for protein function, ligand discovery, and computational methods development. However, relevant conformational states may be missed at common cryogenic (cryo) data-collection temperatures but can be populated at room temperature. To assess the impact of temperature on making structural and computational discoveries, we systematically investigated protein conformational changes in response to temperature and ligand binding in a structural and computational workhorse, the T4 lysozyme L99A cavity. Despite decades of work on this protein, shifting to RT reveals new global and local structural changes. These include uncovering an apo helix conformation that is hidden at cryo but relevant for ligand binding, and altered side chain and ligand conformations. To evaluate the impact of temperature-induced protein and ligand changes on the utility of structural information in computation, we evaluated how temperature can mislead computational methods that employ cryo structures for validation. We find that when comparing simulated structures just to experimental cryo structures, hidden successes and failures often go unnoticed. When using structural information in ligand binding predictions, both coarse docking and rigorous binding free energy calculations are influenced by temperature effects. The trend that cryo artifacts limit the utility of structures for computation holds across five distinct protein classes. Our results suggest caution when consulting cryogenic structural data alone, as temperature artifacts can conceal errors and prevent successful computational predictions, which can mislead the development and application of computational methods in discovering bioactive molecules.
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Registered trials
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