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Stereoelectronic Effects in Stabilizing Protein–N-Glycan Interactions Revealed by Experiment and Machine Learning

The energetics of protein-carbohydrate interactions, central to many life processes, cannot yet be predictably manipulated. This is mostly due to an incomplete quantitative understanding of the enthalpic and entropic basis of these interactions in aqueous solution. Here, we show that stereoelectroni...

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Autores principales: Ardejani, Maziar S., Noodleman, Louis, Powers, Evan T., Kelly, Jeffery W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102341/
https://www.ncbi.nlm.nih.gov/pubmed/33723379
http://dx.doi.org/10.1038/s41557-021-00646-w
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author Ardejani, Maziar S.
Noodleman, Louis
Powers, Evan T.
Kelly, Jeffery W.
author_facet Ardejani, Maziar S.
Noodleman, Louis
Powers, Evan T.
Kelly, Jeffery W.
author_sort Ardejani, Maziar S.
collection PubMed
description The energetics of protein-carbohydrate interactions, central to many life processes, cannot yet be predictably manipulated. This is mostly due to an incomplete quantitative understanding of the enthalpic and entropic basis of these interactions in aqueous solution. Here, we show that stereoelectronic effects contribute significantly to stabilizing protein–N-glycan interactions in the context of a cooperatively folding protein. Double-mutant cycle analyses of the folding data from 52 electronically-varied N-glycoproteins demonstrate an enthalpy-entropy compensation depending on the electronics of the interacting side-chains. Linear and non-linear models obtained using quantum mechanical calculations and machine learning explain up to 79 and 97 % of the experimental interaction energy variability as inferred from the R(2) value of the respective models. Notably, protein-carbohydrate interaction energies strongly correlate with the molecular orbital energy gaps of the interacting substructures. This suggests that stereoelectronic effects must be given a greater weight than previously thought for accurately modelling the short-range dispersive van der Waals interactions between the N-glycan and the protein.
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spelling pubmed-81023412021-09-15 Stereoelectronic Effects in Stabilizing Protein–N-Glycan Interactions Revealed by Experiment and Machine Learning Ardejani, Maziar S. Noodleman, Louis Powers, Evan T. Kelly, Jeffery W. Nat Chem Article The energetics of protein-carbohydrate interactions, central to many life processes, cannot yet be predictably manipulated. This is mostly due to an incomplete quantitative understanding of the enthalpic and entropic basis of these interactions in aqueous solution. Here, we show that stereoelectronic effects contribute significantly to stabilizing protein–N-glycan interactions in the context of a cooperatively folding protein. Double-mutant cycle analyses of the folding data from 52 electronically-varied N-glycoproteins demonstrate an enthalpy-entropy compensation depending on the electronics of the interacting side-chains. Linear and non-linear models obtained using quantum mechanical calculations and machine learning explain up to 79 and 97 % of the experimental interaction energy variability as inferred from the R(2) value of the respective models. Notably, protein-carbohydrate interaction energies strongly correlate with the molecular orbital energy gaps of the interacting substructures. This suggests that stereoelectronic effects must be given a greater weight than previously thought for accurately modelling the short-range dispersive van der Waals interactions between the N-glycan and the protein. 2021-03-15 2021-05 /pmc/articles/PMC8102341/ /pubmed/33723379 http://dx.doi.org/10.1038/s41557-021-00646-w Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Ardejani, Maziar S.
Noodleman, Louis
Powers, Evan T.
Kelly, Jeffery W.
Stereoelectronic Effects in Stabilizing Protein–N-Glycan Interactions Revealed by Experiment and Machine Learning
title Stereoelectronic Effects in Stabilizing Protein–N-Glycan Interactions Revealed by Experiment and Machine Learning
title_full Stereoelectronic Effects in Stabilizing Protein–N-Glycan Interactions Revealed by Experiment and Machine Learning
title_fullStr Stereoelectronic Effects in Stabilizing Protein–N-Glycan Interactions Revealed by Experiment and Machine Learning
title_full_unstemmed Stereoelectronic Effects in Stabilizing Protein–N-Glycan Interactions Revealed by Experiment and Machine Learning
title_short Stereoelectronic Effects in Stabilizing Protein–N-Glycan Interactions Revealed by Experiment and Machine Learning
title_sort stereoelectronic effects in stabilizing protein–n-glycan interactions revealed by experiment and machine learning
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102341/
https://www.ncbi.nlm.nih.gov/pubmed/33723379
http://dx.doi.org/10.1038/s41557-021-00646-w
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