ArticlePLoS computational biology2015
Thermal stabilization of dihydrofolate reductase using monte carlo unfolding simulations and its functional consequences.
Article in PLoS computational biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 43 citations in OpenAlex.
- Pulling and gripping: Proteasomal translocation pathway elements differentially contribute to substrate unfolding.Protein science : a publication of the Protein Society · 2026Article
- FLEXTAG: a small and self-renewable protein labeling system for anti-fading multi-color super-resolution imaging.Nature communications · 2026Article
- FLEXTAG: A Small and Self-renewable Protein Labeling System for Anti-fading Multicolor Super-resolution Imaging.bioRxiv : the preprint server for biology · 2025Article
- Rapid prediction of thermodynamically destabilizing tyrosine phosphorylations in cancers.bioRxiv : the preprint server for biology · 2024Article
- Systematic conformation-to-phenotype mapping via limited deep sequencing of proteins.Molecular cell · 2023Article
- Article
- Evolution avoids a pathological stabilizing interaction in the immune protein S100A9.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders.PLoS computational biology · 2021Article
- Development of antibacterial compounds that constrain evolutionary pathways to resistance.eLife · 2021Article
- Validation of DBFOLD: An efficient algorithm for computing folding pathways of complex proteins.PLoS computational biology · 2020Article
- Article
- Chimeric dihydrofolate reductases display properties of modularity and biophysical diversity.Protein science : a publication of the Protein Society · 2019Article
- Consensus sequence design as a general strategy to create hyperstable, biologically active proteins.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Substrate inhibition imposes fitness penalty at high protein stability.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Bridging the physical scales in evolutionary biology: from protein sequence space to fitness of organisms and populations.Current opinion in structural biology · 2017Review
- An Internal Disulfide Locks a Misfolded Aggregation-prone Intermediate in Cataract-linked Mutants of Human γD-Crystallin.The Journal of biological chemistry · 2016Article
- Thermostability of Enzymes from Molecular Dynamics Simulations.Journal of chemical theory and computation · 2016Article
- Biophysical principles predict fitness landscapes of drug resistance.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Design of proteins with desired thermal properties is important for scientific and biotechnological applications. Here we developed a theoretical approach to predict the effect of mutations on protein stability from non-equilibrium unfolding simulations. We establish a relative measure based on apparent simulated melting temperatures that is independent of simulation length and, under certain assumptions, proportional to equilibrium stability, and we justify this theoretical development with extensive simulations and experimental data. Using our new method based on all-atom Monte-Carlo unfolding simulations, we carried out a saturating mutagenesis of Dihydrofolate Reductase (DHFR), a key target of antibiotics and chemotherapeutic drugs. The method predicted more than 500 stabilizing mutations, several of which were selected for detailed computational and experimental analysis. We find a highly significant correlation of r=0.65-0.68 between predicted and experimentally determined melting temperatures and unfolding denaturant concentrations for WT DHFR and 42 mutants. The correlation between energy of the native state and experimental denaturation temperature was much weaker, indicating the important role of entropy in protein stability. The most stabilizing point mutation was D27F, which is located in the active site of the protein, rendering it inactive. However for the rest of mutations outside of the active site we observed a weak yet statistically significant positive correlation between thermal stability and catalytic activity indicating the lack of a stability-activity tradeoff for DHFR. By combining stabilizing mutations predicted by our method, we created a highly stable catalytically active E. coli DHFR mutant with measured denaturation temperature 7.2°C higher than WT. Prediction results for DHFR and several other proteins indicate that computational approaches based on unfolding simulations are useful as a general technique to discover stabilizing mutations.
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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.