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

Vaitea Opuu; Young Joo Sun; Titus Hou; Nicolas Panel; Ernesto Fuentes; Thomas Simonson

doi:10.1038/s41598-020-67972-w

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

Journal article

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

Vaitea Opuu, Young Joo Sun, Titus Hou, Nicolas Panel, Ernesto Fuentes and Thomas Simonson

Scientific reports, Vol.10(1), pp.11150-11150

07/07/2020

DOI: 10.1038/s41598-020-67972-w

PMCID: PMC7341745

PMID: 32636412

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https://doi.org/10.1038/s41598-020-67972-wView

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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.

Biochemistry, Molecular Biology

Biomolecules

Cellular Biology

Life Sciences

Molecular biology

Details

Title: Subtitle: A physics-based energy function allows the computational redesign of a PDZ domain
Creators: Vaitea Opuu - Institut Polytechnique de Paris
Young Joo Sun - Roy J. and Lucille A. Carver College of Medicine
Titus Hou - Roy J. and Lucille A. Carver College of Medicine
Nicolas Panel - Institut Polytechnique de Paris
Ernesto Fuentes - Roy J. and Lucille A. Carver College of Medicine
Thomas Simonson - Institut Polytechnique de Paris
Resource Type: Journal article
Publication Details: Scientific reports, Vol.10(1), pp.11150-11150
DOI: 10.1038/s41598-020-67972-w
PMID: 32636412
PMCID: PMC7341745
NLM abbreviation: Sci Rep
ISSN: 2045-2322
eISSN: 2045-2322
Publisher: Nature Publishing Group
Language: English
Date published: 07/07/2020
Academic Unit: Biochemistry and Molecular Biology
Record Identifier: 9984293081302771

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