Dataset Information

Amyotrophic Lateral Sclerosis Type 20 - In Silico Analysis and Molecular Dynamics Simulation of hnRNPA1.

ABSTRACT: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and lower motor neurons. 5-10% of cases are genetically inherited, including ALS type 20, which is caused by mutations in the hnRNPA1 gene. The goals of this work are to analyze the effects of non-synonymous single nucleotide polymorphisms (nsSNPs) on hnRNPA1 protein function, to model the complete tridimensional structure of the protein using computational methods and to assess structural and functional differences between the wild type and its variants through Molecular Dynamics simulations. nsSNP, PhD-SNP, Polyphen2, SIFT, SNAP, SNPs&GO, SNPeffect and PROVEAN were used to predict the functional effects of nsSNPs. Ab initio modeling of hnRNPA1 was made using Rosetta and refined using KoBaMIN. The structure was validated by PROCHECK, Rampage, ERRAT, Verify3D, ProSA and Qmean. TM-align was used for the structural alignment. FoldIndex, DICHOT, ELM, D2P2, Disopred and DisEMBL were used to predict disordered regions within the protein. Amino acid conservation analysis was assessed by Consurf, and the molecular dynamics simulations were performed using GROMACS. Mutations D314V and D314N were predicted to increase amyloid propensity, and predicted as deleterious by at least three algorithms, while mutation N73S was predicted as neutral by all the algorithms. D314N and D314V occur in a highly conserved amino acid. The Molecular Dynamics results indicate that all mutations increase protein stability when compared to the wild type. Mutants D314N and N319S showed higher overall dimensions and accessible surface when compared to the wild type. The flexibility level of the C-terminal residues of hnRNPA1 is affected by all mutations, which may affect protein function, especially regarding the protein ability to interact with other proteins.

SUBMITTER: Krebs BB

PROVIDER: S-EPMC4945010 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Amyotrophic Lateral Sclerosis Type 20 - In Silico Analysis and Molecular Dynamics Simulation of hnRNPA1.

Krebs Bruna Baumgarten BB De Mesquita Joelma Freire JF

PloS one 20160714 7

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and lower motor neurons. 5-10% of cases are genetically inherited, including ALS type 20, which is caused by mutations in the hnRNPA1 gene. The goals of this work are to analyze the effects of non-synonymous single nucleotide polymorphisms (nsSNPs) on hnRNPA1 protein function, to model the complete tridimensional structure of the protein using computational methods and to assess structural and functio ...[more]

PMID: 27414033

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Project description:Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disorder, with a significant social and economic burden. ALS remains incurable, and the only drugs approved for its treatments confers a survival benefit of a few months for the patients. Missense mutations in superoxide dismutase 1 (SOD1), a major cytoplasmic antioxidant enzyme, has been associated with ALS development, accounting for 23% of its familial cases and 7% of all sporadic cases. This work aims to characterize in silico the structural and functional effects of SOD1 protein variants. Missense mutations in SOD1 were compiled from the literature and databases. Twelve algorithms were used to predict the functional and stability effects of these mutations. ConSurf was used to estimate the evolutionary conservation of SOD1 amino-acids. GROMACS was used to perform molecular dynamics (MD) simulations of SOD1 wild-type and variants A4V, D90A, H46R, and I113T, which account for approximately half of all ALS-SOD1 cases in the United States, Europe, Japan, and United Kingdom, respectively. 233 missense mutations in SOD1 protein were compiled from the databases and literature consulted. The predictive analyses pointed to an elevated rate of deleterious and destabilizing predictions for the analyzed variants, indicating their harmful effects. The ConSurf analysis suggested that mutations in SOD1 mainly affect conserved and possibly functionally essential amino acids. The MD analyses pointed to flexibility and essential dynamics alterations at the electrostatic and metal-binding loops of variants A4V, D90A, H46R, and I113T that could lead to aberrant interactions triggering toxic protein aggregation. These alterations may have harmful implications for SOD1 and explain their association with ALS. Understanding the effects of SOD1 mutations on protein structure and function facilitates the design of further experiments and provides relevant information on the molecular mechanism of pathology, which may contribute to improvements in existing treatments for ALS.

Project description:BackgroundOne neurodegenerative disorder that is caused by a mutation in the hSOD1 gene is Amyotrophic lateral sclerosis (ALS).ObjectivesThe current study was developed in order to evaluate the effect exerted by two ALS-associated point mutations, L67P and D76Y are located in the metal-binding loop, on structural characterization of hSOD1 protein using molecular dynamics (MD) simulations and computational predictions.Materials and methodsIn this study, GROMACS was utilized to perform molecular dynamics simulations along with 9 different algorithms such as Predict SNP, PhD-SNP, MAPP, PolyPhen-1, Polyphen-2, SNP, SIFT, SNP&GO, and PMUT for predicting and also evaluating the mutational effect on the structural and conformational characterization of hSOD1.ResultsOur study was done by several programs predicting the destabilizing and harmful effect exerted by mutant hSOD1. The deleterious effect of L67P mutation was predicted by MAPP and PhD-SNP algorithms, and D76Y mutation was predicted by 9 algorithms. Comparative studies that were conducted on mutants and wild-type indicated the altar in flexibility and protein conformational stability influenced the metal-binding loop's conformation. The outcomes of the MD exhibited an increase and decrease of flexibility for D76Y and L67P mutants compared to the wild type, respectively. On the other hand, analysis of the gyration radius indicated lower and higher compactness for D76Y and L67P, respectively, suggesting that replacing amino acid at the metal-binding loop can alter the protein compactness compared with the protein the wild type.ConclusionsOverall, these findings provided insight into the effect of mutations on the hSOD1, which leads to neurodegeneration disorders in humans. The results show that the mutations of L67P and D76Y influence the stability of protein conformational and flexibility associated with ALS disease. Thus, results of such mutations are can be a prerequisite to achieve a thorough understanding of ALS pathogenicity.

Dataset Information

Amyotrophic Lateral Sclerosis Type 20 - In Silico Analysis and Molecular Dynamics Simulation of hnRNPA1.

Publications

Amyotrophic Lateral Sclerosis Type 20 - In Silico Analysis and Molecular Dynamics Simulation of hnRNPA1.

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