Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 Mutant
In this work, we investigate the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-barrel of superoxide dismutase 1 (SOD1) in a mutated form,...
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| Format: | Article |
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MDPI AG
2021-11-01
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| Series: | Biology |
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| Online Access: | https://www.mdpi.com/2079-7737/10/12/1240 |
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| author | Stepan Timr Fabio Sterpone |
| author_facet | Stepan Timr Fabio Sterpone |
| author_sort | Stepan Timr |
| collection | DOAJ |
| description | In this work, we investigate the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-barrel of superoxide dismutase 1 (SOD1) in a mutated form, the isoleucine 35 to alanine (I35A) mutant, commonly used as a model system to decipher the role of the full-length apoSOD1 protein in amyotrophic lateral sclerosis (ALS). It is known from experiments that the mutation reduces the stability of the SOD1 barrel and makes it largely unfolded in the cell at 37 degrees Celsius. We deploy state-of-the-art computational machinery to examine the thermal destabilization of the I35A mutant by comparing two widely used force fields, Amber a99SB-disp and CHARMM36m. We find that only the latter force field, when combined with the Replica Exchange with Solute Scaling (REST2) approach, reproduces semi-quantitatively the experimentally observed shift in the melting between the original and the mutated SOD1 barrel. In addition, we analyze the unfolding process and the conformational landscape of the mutant, finding these largely similar to those of the wildtype. Nevertheless, we detect an increased presence of partially misfolded states at ambient temperatures. These states, featuring conformational changes in the region of the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-strands <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>4<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mo>−</mo><mi>β</mi></mrow></semantics></math></inline-formula>6, might provide a pathway for nonnative aggregation. |
| first_indexed | 2024-03-10T04:35:07Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-10T04:35:07Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-d0f6d92be7834fde9b7e6a5ae77451f62023-11-23T03:53:01ZengMDPI AGBiology2079-77372021-11-011012124010.3390/biology10121240Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 MutantStepan Timr0Fabio Sterpone1Laboratoire de Biochimie Théorique (UPR 9080), CNRS, Université de Paris, 13 Rue Pierre et Marie Curie, 75005 Paris, FranceLaboratoire de Biochimie Théorique (UPR 9080), CNRS, Université de Paris, 13 Rue Pierre et Marie Curie, 75005 Paris, FranceIn this work, we investigate the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-barrel of superoxide dismutase 1 (SOD1) in a mutated form, the isoleucine 35 to alanine (I35A) mutant, commonly used as a model system to decipher the role of the full-length apoSOD1 protein in amyotrophic lateral sclerosis (ALS). It is known from experiments that the mutation reduces the stability of the SOD1 barrel and makes it largely unfolded in the cell at 37 degrees Celsius. We deploy state-of-the-art computational machinery to examine the thermal destabilization of the I35A mutant by comparing two widely used force fields, Amber a99SB-disp and CHARMM36m. We find that only the latter force field, when combined with the Replica Exchange with Solute Scaling (REST2) approach, reproduces semi-quantitatively the experimentally observed shift in the melting between the original and the mutated SOD1 barrel. In addition, we analyze the unfolding process and the conformational landscape of the mutant, finding these largely similar to those of the wildtype. Nevertheless, we detect an increased presence of partially misfolded states at ambient temperatures. These states, featuring conformational changes in the region of the <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>-strands <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>β</mi></semantics></math></inline-formula>4<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mo>−</mo><mi>β</mi></mrow></semantics></math></inline-formula>6, might provide a pathway for nonnative aggregation.https://www.mdpi.com/2079-7737/10/12/1240superoxide dismutase 1thermal stabilitymutationmisfoldingmolecular simulations |
| spellingShingle | Stepan Timr Fabio Sterpone Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 Mutant Biology superoxide dismutase 1 thermal stability mutation misfolding molecular simulations |
| title | Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 Mutant |
| title_full | Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 Mutant |
| title_fullStr | Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 Mutant |
| title_full_unstemmed | Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 Mutant |
| title_short | Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 Mutant |
| title_sort | computational insights into the unfolding of a destabilized superoxide dismutase 1 mutant |
| topic | superoxide dismutase 1 thermal stability mutation misfolding molecular simulations |
| url | https://www.mdpi.com/2079-7737/10/12/1240 |
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