Buried Ion-Pairs Reshape Folding Pathways of Artificial Proteins
- 1Stockholm University
Abstract
Ion-pairs are central charged motifs that control the biological function of several proteins. Yet, the physical principles linked to the formation of ion-pairs during protein folding remain poorly understood. Here, we show that buried ion-pairs of de novo-designed helical bundle proteins reshape the folding pathways by introducing kinetic barriers that are overcome by a hydrophobic collapse linked to packing of the protein core. By combining protein design with co-translational folding studies, nuclear magnetic resonance (NMR) spectroscopy, and molecular dynamics simulations, we show that introduction of a buried ion-pair leads to a shifted folding transition that balances desolvation and electrostatic interactions within the protein and the bulk solvent. Moreover, we find that the folding pathway is sensitive to modifications in non-polar interactions and motifs that electrostatically shield the ion-pair from its surroundings. Our combined findings provide a blueprint for understanding how functional motifs affect protein folding and how mutation of charged networks alter the stability of proteins.
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BibTeX
@misc{liebau2026buried,
title = {{Buried Ion-Pairs Reshape Folding Pathways of Artificial Proteins}},
author = {J. Liebau and G. Kemp and D. Auman and N. Hoja and A. Jussupow and M. Baumgart and G. von Heijne and V. R. I. Kaila},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.10.757878},
url = {https://www.biorxiv.org/content/10.64898/2026.10.10.757878v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Buried Ion-Pairs Reshape Folding Pathways of Artificial Proteins
AU - J. Liebau
AU - G. Kemp
AU - D. Auman
AU - N. Hoja
AU - A. Jussupow
AU - M. Baumgart
AU - G. von Heijne
AU - V. R. I. Kaila
PY - 2026
DA - 2026/10/10
PB - bioRxiv
DO - 10.64898/2026.10.10.757878
UR - https://www.biorxiv.org/content/10.64898/2026.10.10.757878v1
AB - Ion-pairs are central charged motifs that control the biological function of several proteins. Yet, the physical principles linked to the formation of ion-pairs during protein folding remain poorly understood. Here, we show that buried ion-pairs of de novo-designed helical bundle proteins reshape the folding pathways by introducing kinetic barriers that are overcome by a hydrophobic collapse linked to packing of the protein core. By combining protein design with co-translational folding studies, nuclear magnetic resonance (NMR) spectroscopy, and molecular dynamics simulations, we show that introduction of a buried ion-pair leads to a shifted folding transition that balances desolvation and electrostatic interactions within the protein and the bulk solvent. Moreover, we find that the folding pathway is sensitive to modifications in non-polar interactions and motifs that electrostatically shield the ion-pair from its surroundings. Our combined findings provide a blueprint for understanding how functional motifs affect protein folding and how mutation of charged networks alter the stability of proteins.
ER -