Computational Insights into How Structural Changes in the Hydrophobic Region of ALS-Linked Mutant SOD1 (G93A) Activate Fluctuations of the Electrostatic Loop: Implications for Aggregation

G93A mutant SOD1 monomers show significantly increased electrostatic loop (loop VII) fluctuations, linked to a hydrogen-bond partner shift at residue 93 and destabilization of V119–L144.

• Why it matters: The mechanism connecting ALS-linked structural changes in SOD1 to aggregation, and how the compensatory I35S mutation suppresses it, is unclear.
• What they did: Molecular dynamics simulations compared wild type, G93A, and the G93A/I35S double mutant monomers, analyzing loop dynamics and hydrogen-bonding, including the 93rd residue partner and the V119–L144 interaction.
• The result: In the G93A background, I35S restores WT-like hydrophobic core packing and reestablishes the V119–L144 hydrogen bond, reducing abnormal electrostatic loop fluctuations and supporting a hydrophobic-region therapeutic strategy for SOD1-linked fALS.

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