Inhibition and Promotion of Chiral Amyloid Self-Assembly on Magnetic Surfaces

Amyloid formation, associated with diseases such as Alzheimer's, Parkinson's, and type II Diabetes, involves the aggregation of soluble proteins and peptides into insoluble fibrils¹. Intercepting the nucleation events that initiate this process is a key strategy for therapeutic intervention. Previous studies have shown that magnetized substrates can alter the self-assembling properties^2,3 and adsorption rates⁴ of chiral biological materials, though they have not yet been applied to amyloid formation. <b><i>Our study explores the use of magnetized substrates to control amyloid self-assembly, leveraging spin-exchange enantiospecific biorecognition interactions.</i></b><br/>Enantiospecific interactions, essential in many biological processes, often exhibit bio-affinity values exceeding theoretical predictions. Our work presents a direct single-molecule measurement of interaction forces between chiral peptides—right- and left-handed helical polyalanine—using atomic force microscopy (AFM)⁵. These measurements, supported by theoretical calculations, show a 70 pN force difference between homochiral and heterochiral peptide pairs attributed to spin exchange interaction caused by the chiral-induced spin selectivity (CISS) effect⁶. The findings highlight the significance of short-range enantiospecific interactions in crowded biological environments.<br/>The newly found short-range spin-exchange enantiospecific interactions led to the investigation of amyloid formation on ferromagnetic substrates magnetized perpendicularly to the surface. We monitored the dynamics and morphology of amyloid formed by electron microscopy and thioflavin T fluorescence assays. The results revealed a preferred magnetization direction for fibril formation, which reversed with the chirality of the monomers—an indicator of the CISS effect. This preferred magnetization resulted in a significantly higher quantity of fibrils, up to twice that of the non-preferred direction, and fibrils that were notably longer, by a factor of up to twenty. Additionally, nucleation occurred more rapidly on the favored magnetization.<br/>Importantly, these trends were consistent across various scales, from the A-beta protein to dipeptides (Ac-Phe2-NH2) and single amino acids (phenylalanine), suggesting a fundamental spin-based driving force in the self-assembly of protein-based chiral systems. Our findings provide new insights into the mechanisms of amyloid formation and highlight the potential of spin and exchange interactions as novel therapeutic targets for amyloid-related diseases.<br/><b>1</b> Knowles, T. P. J. <i>et al.</i> <i>Nat Rev Mol Cell Biol</i> 15, 384–396 (2014)<br/><b>2</b> Al-Bustami, H. <i>et al.</i> <i>Biomacromolecules</i> 23, 2098–2105 (2022)<br/><b>3</b> Tassinari, F. <i>et al.</i> <i>Chem. Sci.</i> 10, 5246–5250 (2019)<br/><b>4</b> Banerjee-Ghosh, K. <i>et al.</i> <i>Science</i> 360, 1331–1334 (2018)<br/><b>5</b> Kapon, Y. <i>et al.</i> <i>Chem</i> 7, 2787–2799 (2021)<br/><b>6</b> Kondou, K. <i>et al.</i> <i>J. Am. Chem. Soc.</i> 144, 7302–7307 (2022)