ArticleScientific reports2020
A physics-based energy function allows the computational redesign of a PDZ domain.
Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Synaptic Ca2+ channels and neurexins are linked through direct and indirect binding complexes.Scientific reports · 2026Article
- Transition State-Based Computational Enzyme Design.Methods in molecular biology (Clifton, N.J.) · 2026Article
- DexDesign: an OSPREY-based algorithm for designing de novo D-peptide inhibitors.Protein engineering, design & selection : PEDS · 2024Article
- 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
- Computational Design of PDZ-Peptide Binding.Methods in molecular biology (Clifton, N.J.) · 2021Article
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Computational protein design (CPD) can address the inverse folding problem, exploring a large space of sequences and selecting ones predicted to fold. CPD was used previously to redesign several proteins, employing a knowledge-based energy function for both the folded and unfolded states. We show that a PDZ domain can be entirely redesigned using a "physics-based" energy for the folded state and a knowledge-based energy for the unfolded state. Thousands of sequences were generated by Monte Carlo simulation. Three were chosen for experimental testing, based on their low energies and several empirical criteria. All three could be overexpressed and had native-like circular dichroism spectra and 1D-NMR spectra typical of folded structures. Two had upshifted thermal denaturation curves when a peptide ligand was present, indicating binding and suggesting folding to a correct, PDZ structure. Evidently, the physical principles that govern folded proteins, with a dash of empirical post-filtering, can allow successful whole-protein redesign.
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Registered trials
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