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In Silico Determined Properties of Designed Superoxide Dismutase-1 Mutants Predict ALS-like Phenotypes In Vitro and In Vivo

By Michèle G. DuVal, McAlary L., Mona Habibi, Pranav Garg, Mine Sher, Neil R. Cashman, W. Ted Allison, Steven S Plotkin

Posted 20 Nov 2018
bioRxiv DOI: 10.1101/474585

The underlying physical causes of SOD1-related ALS are still not well-understood. We address this problem here by computationally designing two de novo mutants, A89R and K128N, which were predicted theoretically to be either significantly destabilizing or stabilizing respectively. We subjected these in silico designed mutants to a series of experimental tests, including in vitro measures of thermodynamic stability, cell-based aggregation and toxicity assays, and an in vivo developmental model of zebrafish motor neuron axonopathy. The experimental tests validated the theoretical predictions: A89R is an unstable, highly-deleterious mutant, and K128N is a stable, non-toxic mutant. Moreover, K128N is predicted computationally to form an unusually stable heterodimer with the familial ALS mutant A4V. Consistent with this prediction, co-injection of K128N and A4V into zebrafish shows profound rescue of motor neuron pathology. The demonstrated success of these first principles calculations to predict the physical properties of SOD1 mutants holds promise for rationally designed therapies to counter the progression of ALS.

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