Engineering Water-Soluble Synaptic Vesicle Proteins

Our new research detailing the architecture of synaptic vesicle proteins and their engineered water-soluble variants is now published. These proteins are fundamental for neurotransmitter release but remain notoriously difficult to study due to their complex location within the cell membrane.

Conducted by Taner Karagöl, Alper Karagöl and Prof. Shuguang Zhang at the Massachusetts Institute of Technology, this study focuses on the structural mechanics of key proteins like synaptophysin, synaptogyrins, and the SV2 family.

To overcome this membrane constraint, we applied the QTY code to engineer water-soluble variants. By systematically replacing hydrophobic amino acids with hydrophilic ones, we achieved up to 55 percent sequence alteration in the transmembrane domains. Despite these significant changes, the variants maintained structural similarity with the native folds, demonstrating RMSD values strictly below 1.9 Å. Through molecular dynamics simulations, we evaluated the structural stability and conformational dynamics of both the native proteins and the newly engineered variants.

One of our central (but unexpected) findings was the discovery of a strong evolutionary relationship between threonine and valine frequencies in homologous sequences. This coupling persists despite the high mutational barrier requiring a double-nucleotide change, indicating a functional evolutionary necessity. Ultimately, our data indicate that engineering water-soluble synaptic vesicle proteins provides valuable new tools for structural biology, evolutionary studies, and the advancement of targeted therapeutic strategies for neurological conditions.

Karagöl, T., Karagöl, A., & Zhang, S. (2026). Integrative Structural Bioinformatics and Molecular Dynamics Analyses of Synaptic Vesicle Proteins and Their Water-Soluble QTY-Variants Reveal Membrane Constraints and Evolutionary Coupling of T⇔ V. Journal of Molecular Evolution, 1-22. https://doi.org/10.1007/s00239-026-10315-6

PubMed: https://pubmed.ncbi.nlm.nih.gov/42086760/