Amyotrophic Lateral Sclerosis Type 20 - In Silico Analysis and Molecular Dynamics Simulation of hnRNPA1
| Autor: | Joelma Freire De Mesquita, Bruna Baumgarten Krebs |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Protein Structure Comparison Heterogeneous Nuclear Ribonucleoprotein A1 Mutant lcsh:Medicine Protein Structure Prediction medicine.disease_cause Biochemistry Motor Neuron Diseases Protein structure Heterogeneous-Nuclear Ribonucleoprotein Group A-B Macromolecular Structure Analysis Medicine and Health Sciences Biochemical Simulations lcsh:Science Genetics Mutation Multidisciplinary Molecular Structure Applied Mathematics Simulation and Modeling Neurodegenerative Diseases Protein structure prediction Deletion Mutation Neurology Physical Sciences Amino Acid Analysis Algorithms Research Article Protein Structure In silico Structural alignment Single-nucleotide polymorphism Biology Molecular Dynamics Simulation Research and Analysis Methods Polymorphism Single Nucleotide 03 medical and health sciences medicine Humans Computer Simulation Molecular Biology Techniques Molecular Biology Molecular Biology Assays and Analysis Techniques lcsh:R Amyotrophic Lateral Sclerosis Wild type Biology and Life Sciences Proteins Computational Biology 030104 developmental biology lcsh:Q Mathematics |
| Zdroj: | PLoS ONE PLoS ONE, Vol 11, Iss 7, p e0158939 (2016) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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