ArticleJournal of molecular biology2007
High-resolution structural and thermodynamic analysis of extreme stabilization of human procarboxypeptidase by computational protein design.
Article in Journal of molecular biology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 90 citations in OpenAlex.
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- Selection pressures on evolution of ribonuclease H explored with rigorous free-energy-based design.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Computationally Guided Redesign of a Heme-free Cytochrome with Native-like Structure and Stability.Biochemistry · 2022Article
- The stability and dynamics of computationally designed proteins.Protein engineering, design & selection : PEDS · 2022Review
- A strategy for proline and glycine mutations to proteins with alchemical free energy calculations.Journal of computational chemistry · 2021Article
- A physics-based energy function allows the computational redesign of a PDZ domain.Scientific reports · 2020Article
- Molecular dynamics simulations suggest stabilizing mutations in a de novo designed α/β protein.Protein engineering, design & selection : PEDS · 2019Article
- Computer-aided design of amino acid-based therapeutics: a review.Drug design, development and therapy · 2018Review
- Comparison of Five Protein Engineering Strategies for Stabilizing an α/β-Hydrolase.Biochemistry · 2017Article
- Collective repacking reveals that the structures of protein cores are uniquely specified by steric repulsive interactions.Protein engineering, design & selection : PEDS · 2017Article
- A critical analysis of computational protein design with sparse residue interaction graphs.PLoS computational biology · 2017Article
- Balancing Selectivity and Efficacy of Bispecific Epidermal Growth Factor Receptor (EGFR) × c-MET Antibodies and Antibody-Drug Conjugates.The Journal of biological chemistry · 2016Article
- Computational Redesign of Thioredoxin Is Hypersensitive toward Minor Conformational Changes in the Backbone Template.Journal of molecular biology · 2016Article
- Fast, cheap and out of control--Insights into thermodynamic and informatic constraints on natural protein sequences from de novo protein design.Biochimica et biophysica acta · 2016Article
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- Redesign of the monomer-monomer interface of Cre recombinase yields an obligate heterotetrameric complex.Nucleic acids research · 2015Article
- Application of Enhanced Sampling Monte Carlo Methods for High-Resolution Protein-Protein Docking in Rosetta.PloS one · 2015Article
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- Hydrophobic substitution of surface residues affects lipase stability in organic solvents.Molecular biotechnology · 2014Article
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Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Recent efforts to design de novo or redesign the sequence and structure of proteins using computational techniques have met with significant success. Most, if not all, of these computational methodologies attempt to model atomic-level interactions, and hence high-resolution structural characterization of the designed proteins is critical for evaluating the atomic-level accuracy of the underlying design force-fields. We previously used our computational protein design protocol RosettaDesign to completely redesign the sequence of the activation domain of human procarboxypeptidase A2. With 68% of the wild-type sequence changed, the designed protein, AYEdesign, is over 10 kcal/mol more stable than the wild-type protein. Here, we describe the high-resolution crystal structure and solution NMR structure of AYEdesign, which show that the experimentally determined backbone and side-chains conformations are effectively superimposable with the computational model at atomic resolution. To isolate the origins of the remarkable stabilization, we have designed and characterized a new series of procarboxypeptidase mutants that gain significant thermodynamic stability with a minimal number of mutations; one mutant gains more than 5 kcal/mol of stability over the wild-type protein with only four amino acid changes. We explore the relationship between force-field smoothing and conformational sampling by comparing the experimentally determined free energies of the overall design and these focused subsets of mutations to those predicted using modified force-fields, and both fixed and flexible backbone sampling protocols.
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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.