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A physics-based energy function allows the computational redesign of a PDZ domain

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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https://hal-polytechnique.archives-ouvertes.fr/hal-02988336
Contributor : Aurélien Arnoux <>
Submitted on : Wednesday, November 4, 2020 - 4:48:45 PM
Last modification on : Thursday, November 5, 2020 - 3:33:10 AM

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Vaitea Opuu, Young Joo Sun, Titus Hou, Nicolas Panel, Ernesto Fuentes, et al.. A physics-based energy function allows the computational redesign of a PDZ domain. Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.11150. ⟨10.1038/s41598-020-67972-w⟩. ⟨hal-02988336⟩

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