Free energy calculations of ALS‐causing SOD1 mutants reveal common perturbations to stability and dynamics along the maturation pathway

• Published in: Protein science Vol. 30; no. 9; pp. 1804 - 1817
• Main Authors: Wells, Nicholas G. M., Tillinghast, Grant A., O'Neil, Alison L., Smith, Colin A.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-09-2021; Wiley Subscription Services, Inc
• Subjects: Allosteric properties; Allosteric Regulation; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Apoproteins - chemistry; Apoproteins - genetics; Apoproteins - metabolism; Binding Sites; Cations, Divalent; Coupling (molecular); Dimers; Dynamic stability; Free energy; free energy calculations; Full‐Length Paper; Full‐Length Papers; Gene Expression; Humans; Hydrogen Bonding; Kinetics; Maturation; metal binding; Molecular Dynamics Simulation; Mutation; Neurotoxicity; Perturbation; Protein Aggregates; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; protein dynamics; Protein interaction; Protein Interaction Domains and Motifs; Protein Multimerization; Superoxide dismutase; superoxide dismutase 1; Superoxide Dismutase-1 - chemistry; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; Therapeutic targets; Thermodynamic coupling; Thermodynamics; Zinc - chemistry; Zinc - metabolism; metal binding; free energy calculations; amyotrophic lateral sclerosis; superoxide dismutase 1; protein dynamics
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1002/pro.4132

With over 150 heritable mutations identified as disease‐causative, superoxide dismutase 1 (SOD1) has been a main target of amyotrophic lateral sclerosis (ALS) research and therapeutic efforts. However, recent evidence has suggested that neither loss of function nor protein aggregation is responsible for promoting neurotoxicity. Furthermore, there is no clear pattern to the nature or the location of these mutations that could suggest a molecular mechanism behind SOD1‐linked ALS. Here, we utilize reliable and accurate computational techniques to predict the perturbations of 10 such mutations to the free energy changes of SOD1 as it matures from apo monomer to metallated dimer. We find that the free energy perturbations caused by these mutations strongly depend on maturational progress, indicating the need for state‐specific therapeutic targeting. We also find that many mutations exhibit similar patterns of perturbation to native and non‐native maturation, indicating strong thermodynamic coupling between the dynamics at various sites of maturation within SOD1. These results suggest the presence of an allosteric network in SOD1 which is vulnerable to disruption by these mutations. Analysis of these perturbations may contribute to uncovering a unifying molecular mechanism which explains SOD1‐linked ALS and help to guide future therapeutic efforts.