article published yes Zenon Toprakcioglu author Ayaka Kamada author Thomas C.T. Michaels author Mengqi Xie author Johannes Krausser author Jiapeng Wei author Anđela Šarić author bf63d406-f056-11eb-b41d-f263a6566d8b0000-0002-7854-2139 Michele Vendruscolo author Tuomas P.J. Knowles author AnSa department Non-Equilibrium Protein Assembly: from Building Blocks to Biological Machines project Primary nucleation is the fundamental event that initiates the conversion of proteins from their normal physiological forms into pathological amyloid aggregates associated with the onset and development of disorders including systemic amyloidosis, as well as the neurodegenerative conditions Alzheimer’s and Parkinson’s diseases. It has become apparent that the presence of surfaces can dramatically modulate nucleation. However, the underlying physicochemical parameters governing this process have been challenging to elucidate, with interfaces in some cases having been found to accelerate aggregation, while in others they can inhibit the kinetics of this process. Here we show through kinetic analysis that for three different fibril-forming proteins, interfaces affect the aggregation reaction mainly through modulating the primary nucleation step. Moreover, we show through direct measurements of the Gibbs free energy of adsorption, combined with theory and coarse-grained computer simulations, that overall nucleation rates are suppressed at high and at low surface interaction strengths but significantly enhanced at intermediate strengths, and we verify these regimes experimentally. Taken together, these results provide a quantitative description of the fundamental process which triggers amyloid formation and shed light on the key factors that control this process. https://research-explorer.ista.ac.at/download/11841/14386/2022_PNAS_Toprakcioglu.pdf application/pdfno https://creativecommons.org/licenses/by-nc-nd/4.0/ National Academy of Sciences2022 eng 0027-8424 1091-6490 35901206 00090375350000210.1073/pnas.2109718119 11931 Toprakcioglu, Z., Kamada, A., Michaels, T. C. T., Xie, M., Krausser, J., Wei, J., … Knowles, T. P. J. (2022). Adsorption free energy predicts amyloid protein nucleation rates. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences. <a href="https://doi.org/10.1073/pnas.2109718119">https://doi.org/10.1073/pnas.2109718119</a> Toprakcioglu Z, Kamada A, Michaels TCT, Xie M, Krausser J, Wei J, Šarić A, Vendruscolo M, Knowles TPJ. 2022. Adsorption free energy predicts amyloid protein nucleation rates. Proceedings of the National Academy of Sciences of the United States of America. 119(31), e2109718119. Toprakcioglu, Zenon, Ayaka Kamada, Thomas C.T. Michaels, Mengqi Xie, Johannes Krausser, Jiapeng Wei, Anđela Šarić, Michele Vendruscolo, and Tuomas P.J. Knowles. “Adsorption Free Energy Predicts Amyloid Protein Nucleation Rates.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>. National Academy of Sciences, 2022. <a href="https://doi.org/10.1073/pnas.2109718119">https://doi.org/10.1073/pnas.2109718119</a>. Z. Toprakcioglu, A. Kamada, T.C.T. Michaels, M. Xie, J. Krausser, J. Wei, A. Šarić, M. Vendruscolo, T.P.J. Knowles, Proceedings of the National Academy of Sciences of the United States of America 119 (2022). Toprakcioglu, Zenon, et al. “Adsorption Free Energy Predicts Amyloid Protein Nucleation Rates.” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 119, no. 31, e2109718119, National Academy of Sciences, 2022, doi:<a href="https://doi.org/10.1073/pnas.2109718119">10.1073/pnas.2109718119</a>. Toprakcioglu Z, Kamada A, Michaels TCT, et al. Adsorption free energy predicts amyloid protein nucleation rates. <i>Proceedings of the National Academy of Sciences of the United States of America</i>. 2022;119(31). doi:<a href="https://doi.org/10.1073/pnas.2109718119">10.1073/pnas.2109718119</a> Z. Toprakcioglu <i>et al.</i>, “Adsorption free energy predicts amyloid protein nucleation rates,” <i>Proceedings of the National Academy of Sciences of the United States of America</i>, vol. 119, no. 31. National Academy of Sciences, 2022. 118412022-08-14T22:01:45Z2025-06-12T06:21:34Z