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Several different mutations of the protein copper, zinc superoxide dismutase (SOD1) produce the neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The molecular mechanism by which the diverse mutations converge to a similar pathology is currently unknown. The electrostatic loop (EL) of SOD1 is known to be affected in all of the studied ALS-linked mutations of SOD1. In this work, we employ a multiscale simulation approach to show that this perturbation corresponds to an increased probability of the EL detaching from its native position, exposing the metal site of the protein to water. From extensive atomistic and coarse-grained molecular dynamics (MD) simulations, we identify an allosteric pathway that explains the action of the distant G93A mutation on the EL. Finally, we employ quantum mechanics/molecular mechanics MD simulations to show that the opening of the EL decreases the Zn(II) affinity of the protein. As the loss of Zn(II) is at the center of several proposed pathogenic mechanisms in SOD1-linked ALS, the structural effect identified here not only is in agreement with the experimental data but also places the opening of the electrostatic loop as the possible main pathogenic effect for a significant number of ALS-linked SOD1 mutations. T protein copper, zinc superoxide dismutase (SOD1) catalyzes the dismutation of the superoxide radical into molecular oxygen and peroxide. It protects the cell from the radical, which is naturally formed during cell respiration. Human SOD1 is a dimeric protein, which binds a Zn(II) and a Cu(I/II) ion per monomer (see Figure 1A,B). Well more than 100 mutations, scattered along the whole sequence of SOD1, are linked to familial forms of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). The study of SOD1-linked cases of ALS is expected to shed light on the pathogenic mechanism of the most prevalent sporadic form of the disease. The pathogenic mechanisms of the ALS-linked mutations of SOD1 have not been elucidated in detail. The current data indicate that a gain of a pathological function is responsible for the toxicity of the mutant, rather than a loss of enzymatic activity. Several hypotheses for the pathological function exist: SOD1 misfolding could interfere with cellular metabolism. A distortion of the active site of the protein could cause aberrant redox catalysis and cellular oxidative stress. Finally, a loss of metal ions, particularly Zn(II), from the SOD1 active site, could cause a harmful metal dyshomeostasis. A loss of Zn(II) from the active site of SOD1 appears to play a critical role in the hypotheses for SOD1 pathogenicity: It destabilizes the protein’s structure and alters its active site, and mutant SOD1 has been shown to cause Zn(II) dyshomeostasis in mice. Close to the Zn(II) site of SOD1 is the electrostatic loop (EL), which is known to be destabilized in several ALS-linked mutants. From a physicochemical point of view, the diversity of the pathogenic mutations, regarding both the amino acid substitution and its location in the protein structure, is intriguing. Because demetalation has been shown to be important for the misfolding process, computational investigation of pathogenic mutants of SOD1 has been preferentially performed on the zinc-deficient apoenzyme, confirming that ALS-linked mutations also increase the level of oligomerization. Mera-Adasme and collaborators have investigated the effect of SOD1 mutations on the metal site by means of computational chemistry. Their focus was exclusively on mutations in the proximity of the metal site, Received: September 28, 2019 Accepted: November 20, 2019 Published: November 20, 2019 Letter pubs.acs.org/JPCL Cite This: J. Phys. Chem. Lett. 2019, 10, 7740−7744 © 2019 American Chemical Society 7740 DOI: 10.1021/acs.jpclett.9b02868 J. Phys. Chem. Lett. 2019, 10, 7740−7744 This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes. D ow nl oa de d vi a U N IV G R O N IN G E N o n Ja nu ar y 8, 2 02 0 at 0 9: 37 :2 4 (U T C ). Se e ht tp s: //p ub s. ac s. or g/ sh ar in gg ui de lin es f or o pt io ns o n ho w to le gi tim at el y sh ar e pu bl is he d ar tic le s.

An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation