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As a supramolecular ligand that binds to lysine and arginine residues, the molecular tweezer CLR01 was found to modify the aggregation pathway of disease\u2010relevant proteins <jats:italic>in\u2005vitro<\/jats:italic> and <jats:italic>in\u2005vivo<\/jats:italic> with beneficial effects on toxicity. However, the molecular mechanisms of how tweezers exert these effects remain mainly unknown, hampering further drug development. Here, we investigate the modulation mechanism of unfolding and aggregation pathways of SOD1, which are involved in amyotrophic lateral sclerosis (ALS), by CLR01. Using a truncated version of the wildtype SOD1 protein, SOD1<jats:sub>bar<\/jats:sub>, we show that CLR01 acts on the first step of the aggregation pathway, the unfolding of the SOD1 monomer. CLR01 increases, by \u223c10\u2009\u00b0C, the melting temperatures of the A4V and G41D SOD1 mutants, which are commonly observed mutations in familial ALS. Molecular dynamics simulations and binding free energy calculations as well as native mass spectrometry and mutational studies allowed us to identify K61 and K92 as binding sites for the tweezers to mediate the stability increase. The data suggest that the modulation of SOD1 conformational stability is a promising target for future developments of supramolecular ligands against neurodegenerative diseases.<\/jats:p>","DOI":"10.1002\/cbic.202200396","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T17:21:22Z","timestamp":1662744082000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Superoxide Dismutase 1 Folding Stability as a Target for Molecular Tweezers in SOD1\u2010Related Amyotrophic Lateral Sclerosis"],"prefix":"10.1002","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5746-6907","authenticated-orcid":false,"given":"Nirnay","family":"Samanta","sequence":"first","affiliation":[{"name":"Institute of Physical and Theoretical Chemistry TU Braunschweig  38106 Braunschweig Germany"},{"name":"Braunschweig Integrated Centre of Systems Biology (BRICS) 38106  Braunschweig 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