Buried Ion-Pairs Reshape Folding Pathways of Artificial Proteins
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…
Ion-pairs, charged motifs, play a crucial role in controlling the function of several proteins. However, the underlying physical principles behind the formation of ion-pairs during protein folding are not well understood. In this study, researchers demonstrate that buried ion-pairs in newly designed helical bundle proteins alter the folding pathways by introducing kinetic barriers. These barriers are eventually overcome through a hydrophobic collapse associated with the protein core's packing.
The researchers employed a combination of protein design, co-translational folding studies, nuclear magnetic resonance (NMR) spectroscopy, and molecular dynamics simulations to reach their findings. They discovered that introducing a buried ion-pair leads to a shifted folding transition, striking a balance between desolvation and electrostatic interactions within the protein and the surrounding solvent.
Additionally, the folding pathway proves to be sensitive to changes in non-polar interactions and motifs that shield the ion-pair from its environment.
The authors' combined results offer a framework for comprehending how functional motifs influence protein folding and how alterations in charged networks impact protein stability.
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