A physics-based energy function allows the computational redesign of a PDZ domain
| العنوان: | A physics-based energy function allows the computational redesign of a PDZ domain |
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| المؤلفون: | Young Joo Sun, Carlos Corbi-Verge, Nicolas Panel, Vaitea Opuu, Philip M. Kim, Titus Hou, Thomas Simonson, Marcus B. Noyes, David M. Ichikawa, Ernesto J. Fuentes |
| المساهمون: | Laboratoire de Biologie Structurale de la Cellule (BIOC), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Carver College of Medicine [Iowa City], University of Iowa [Iowa City] |
| المصدر: | Scientific Reports, Vol 10, Iss 1, Pp 1-9 (2020) Scientific Reports Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.11150. ⟨10.1038/s41598-020-67972-w⟩ |
| بيانات النشر: | Nature Publishing Group, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Thermal denaturation, Fold (higher-order function), Computer science, Monte Carlo method, Protein design, PDZ domain, lcsh:Medicine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 010402 general chemistry, Molecular mechanics, 01 natural sciences, Article, Inverse folding, Protein sequencing, Protein structure, Experimental testing, Animal disease models, 0103 physical sciences, Statistical physics, lcsh:Science, Peptide ligand, Biological models, chemistry.chemical_classification, Physics, Multidisciplinary, 010304 chemical physics, Ligand, lcsh:R, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Physics based, Circular dichroism spectra, Amino acid, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 0104 chemical sciences, chemistry, lcsh:Q, Biological system |
| الوصف: | A powerful approach to understand protein structure and evolution is to perform computer simulations that mimic aspects of evolution. In particular, structure-based computational protein design (CPD) can address the inverse folding problem, exploring a large space of amino acid sequences and selecting ones predicted to adopt a given fold. Previously, CPD has been used to entirely redesign several proteins: all or most of the protein sequence was allowed to mutate freely; among sampled sequences, those with low computed folding energy were selected, and a few percent of them did indeed adopt the correct fold. Those studies used an energy function that was partly or largely knowledge-based, with several empirical terms. Here, we show that a PDZ domain can be entirely redesigned using a "physics-based" energy function that combines standard molecular mechanics and a recent, continuum electrostatic solvent model. Many thousands of sequences were generated by Monte Carlo simulation. Among the lowest-energy sequences, three were chosen for experimental testing. All three could be overexpressed and had native-like circular dichroism and 1D NMR spectra. Two exhibited an upshift of their thermal denaturation curves when a peptide ligand was present, indicating they were able to bind and were most likely correctly folded. Evidently, the physical principles that govern molecular mechanics and continuum electrostatics are sufficient to perform whole-protein redesign. This is encouraging, since these methods provide physical insights, can be systematically improved, and are transferable to other biopolymers and ligands of medical or technological interest. |
| اللغة: | English |
| تدمد: | 2045-2322 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c547ce2f6433948eaa712562e8d22676Test http://link.springer.com/article/10.1038/s41598-020-67972-wTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c547ce2f6433948eaa712562e8d22676 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
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