ArticleProceedings of the National Academy of Sciences of the United States of America2013
Rational modification of protein stability by targeting surface sites leads to complicated results.
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 27 papers.
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Who cites it
27 citing papers in PubMed.
- Characterization of the pH-Dependent Stabilizing Forces of Insulin's Native and Fibril States.ACS physical chemistry Au · 2026Article
- Computational optimization of DEK1 calpain domain solubility through integrated structural modelling and data-driven targeted mutagenesis.Scientific reports · 2026Article
- GPU-Accelerated Implementation of Constant-pH Molecular Dynamics in NAMD.Journal of chemical information and modeling · 2025Article
- Ancestral Sequence Reconstruction to Accelerate Non-heme Iron-dependent Biocatalyst Engineering.ACS central science · 2025Article
- Understanding the stability landscape of LbCas12a by deep analysis of stabilizing mutations and mutation combinations.Protein science : a publication of the Protein Society · 2025Article
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- Prediction of protein pChemical science · 2022Article
- Protein pACS omega · 2021Article
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- Quantitative Analysis of Protein Unfolded State Energetics: Experimental and Computational Studies Demonstrate That Non-Native Side-Chain Interactions Stabilize Local Native Backbone Structure.The journal of physical chemistry. B · 2021Article
- Ion-Pair Interaction and Hydrogen Bonds as Main Features of Protein Thermostability in Mutated T1 Recombinant Lipase Originating fromMolecules (Basel, Switzerland) · 2020Article
- Folding Free Energy Landscape of Ordered and Intrinsically Disordered Proteins.Scientific reports · 2019Article
- Modulation of allosteric coupling by mutations: from protein dynamics and packing to altered native ensembles and function.Current opinion in structural biology · 2019Review
- Fast Pairwise Approximation of Solvent Accessible Surface Area for Implicit Solvent Simulations of Proteins on CPUs and GPUs.Journal of chemical theory and computation · 2018Article
- Generalized Born Based Continuous Constant pH Molecular Dynamics in Amber: Implementation, Benchmarking and Analysis.Journal of chemical information and modeling · 2018Article
- A new structural arrangement in proteins involving lysine NHScientific reports · 2017Article
- Proton-Coupled Conformational Allostery Modulates the Inhibitor Selectivity for β-Secretase.The journal of physical chemistry letters · 2017Article
- Global analysis of protein folding using massively parallel design, synthesis, and testing.Science (New York, N.Y.) · 2017Article
- Insights from molecular dynamics simulations for computational protein design.Molecular systems design & engineering · 2017Article
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Authors and funding
6 authors.
Funding
Abstract
The rational modification of protein stability is an important goal of protein design. Protein surface electrostatic interactions are not evolutionarily optimized for stability and are an attractive target for the rational redesign of proteins. We show that surface charge mutants can exert stabilizing effects in distinct and unanticipated ways, including ones that are not predicted by existing methods, even when only solvent-exposed sites are targeted. Individual mutation of three solvent-exposed lysines in the villin headpiece subdomain significantly stabilizes the protein, but the mechanism of stabilization is very different in each case. One mutation destabilizes native-state electrostatic interactions but has a larger destabilizing effect on the denatured state, a second removes the desolvation penalty paid by the charged residue, whereas the third introduces unanticipated native-state interactions but does not alter electrostatics. Our results show that even seemingly intuitive mutations can exert their effects through unforeseen and complex interactions.
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