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

Krebs, Bruna Baumgarten; Mesquita, Joelma Freire De

doi:10.1371/journal.pone.0158939

Cited by 38 publications

(90 citation statements)

References 65 publications

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“…It is worth mentioning, that methods, applied in this study, have been used in similar experiments with other proteins. For example, Krebs and co‐authors successfully conducted in silico experiments, using ROSETTA software package for de novo modeling of the hnRNPA1 protein tertiary structure and assessing structural and functional differences between the wild type and its variants …”

Section: Resultsmentioning

confidence: 99%

Complex formation dynamics of native and mutated pyrin's B30.2 domain with caspase‐1

Arakelov

Nazaryan

2018

Proteins

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Pyrin protein is the product of the MEFV gene, mutations in which cause manifestation of familial Mediterranean fever (FMF). Functions of pyrin are not completely clear. The secondary structure of the pyrin is represented with four domains and two motifs. Mutations p.M680I, p.M694V, p.M694I, p.K695R, p.V726A, and p.A744S, which are located in the B30.2 domain of pyrin protein, are responsible for manifestation of the most common and severe forms of FMF. All the domains and the motifs of pyrin, are directly or indirectly, involved in the protein-protein interaction with proteins of apoptosis and regulate the cascade of inflammatory reactions, which is impaired due to pyrin mutations. It is well known, that malfunction of the pyrin-caspase-1 complex is the main reason of inflammation during FMF. Complete tertiary structure of pyrin and the effects of mutations in it are experimentally not studied yet. The aim of this study was to identify possible effects of the abovementioned mutations in the B30.2 domain tertiary structure and to determine their potential consequences in formation of the B30.2-caspase-1 complex. Using in silico methods, it was found, that these mutations led to structural rearrangements in B30.2 domain tertiary structure, causing shifts of binding sites and altering the interaction energy between B30.2 and caspase-1.

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Section: Resultsmentioning

confidence: 99%

Complex formation dynamics of native and mutated pyrin's B30.2 domain with caspase‐1

Arakelov

Nazaryan

2018

Proteins

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“…Complete wild‐type SOD3 structures were created based on comparative and ab initio modeling by submitting the sequence of the SOD3 protein (ID: P08294) on Modeller, Swiss Model, Rosetta and I‐Tasser algorithms. Modeller was used through MholLine workflow (http://www.mholline.lncc.br/), while I‐Tasser, SwissModel and Robetta algorithms were used through the I‐Tasser (http://zhanglab.ccmb.med.umich.edu/I-TASSER/, RRID:SCR_014627), SwissModel (https://swissmodel.expasy.org/) and Robetta (http://robetta.bakerlab.org/) servers, respectively.…”

Section: Methodsmentioning

confidence: 99%

In silico analysis and molecular dynamics simulation of human superoxide dismutase 3 (SOD3) genetic variants

Pereira

Silva

Nascimento

et al. 2018

J of Cellular Biochemistry

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Oxidative stress is a major factor in aging processes. Superoxide dismutase 3 (SOD3) plays a key role in the protection of extracellular oxidative stress. Missense mutations in SOD3 have been described to be associated with the occurrence of pulmonary, cardiovascular, and neoplastic diseases. This study aims to analyze the effects of missense mutations on the SOD3 structure and function by modeling a complete SOD3 structure as well as analyzing the differences between the wild-types and mutants using computational simulations. Here, ten algorithms were used to predict the structural and functional effects of missense mutations. A complete model of SOD3 protein was made by ab initio and comparative modeling using the Rosetta algorithm and validated by PROCHECK, Verify 3D, QMEAN, and ProSa. Molecular dynamics (MD) simulations were performed and analyzed using the GROMACS package. The deleterious potential of the A58T and R231G mutants was not predicted by the majority of the used algorithms. The analyzed mutations were predicted as destabilizing by at least one algorithm. The MD analyses indicated that protein flexibility may be increased by all of the analyzed mutations, while the protein-ligand stability may be decreased. They also suggested that the variants A91T and R231G increase the overall dimensions of SOD3 and decrease its accessible surface area. Our findings, therefore, indicated that the analyzed mutations could affect the protein structure and its ability to interact with other molecules, which may be related to the functional impairment of SOD3 upon A58T and R231G mutations, as well as their involvement in pathologies.

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“…The MD simulation is an in silico method of solving Newtonian equations of motion for a group of atoms [26]. This method describes the variation of molecular movement over time and can be used to reproduce the behavior of proteins in their biological environment [14]. During an MD simulation, the interatomic interactions of a given molecular system are calculated over time.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

“…Although millions of novel genetic variants are currently being discovered by next-generation sequencing projects [18], the characterization of their effects is extremely expensive, timeconsuming and difficult when using wet-lab experiments [16]. Computational prediction methods, which are less expensive and faster but accurate, allow the prioritization of the most likely disease-related mutations to be thoroughly examined with experiments, thereby saving time and resources [14]. Computational prediction methods can also be applied to the study of already known disease-related mutations.…”

Section: Plos Onementioning

confidence: 99%

“…Computer simulations can perform predictions with a variety of purposes, such as predicting the effect of mutations on proteins and modeling their three-dimensional structures in a better cost/efficiency, faster butaccurate manner [14]. Thus, this method has become an effective approach for studying disease-related mutations and their implications for protein structure and function [15].…”

Section: Introductionmentioning

confidence: 99%

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In silico analysis of the tryptophan hydroxylase 2 (TPH2) protein variants related to psychiatric disorders

et al. 2020

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The tryptophan hydroxylase 2 (TPH2) enzyme catalyzes the first step of serotonin biosynthesis. Serotonin is known for its role in several homeostatic systems related to sleep, mood, and food intake. As the reaction catalyzed by TPH2 is the rate-limiting step of serotonin biosynthesis, mutations in TPH2 have been associated with several psychiatric disorders (PD). This work undertakes an in silico analysis of the effects of genetic mutations in the human TPH2 protein. Ten algorithms were used to predict the functional and stability effects of the TPH2 mutations. ConSurf was used to estimate the evolutionary conservation of TPH2 amino acids. GROMACS was used to perform molecular dynamics (MD) simulations of TPH2 WT and P260S, R303W, and R441H, which had already been associated with the development of PD. Forty-six TPH2 variants were compiled from the literature. Among the analyzed variants, those occurring at the catalytic domain were shown to be more damaging to protein structure and function. The ConSurf analysis indicated that the mutations affecting the catalytic domain were also more conserved throughout evolution. The variants S364K and S383F were predicted to be deleterious by all the functional algorithms used and occurred at conserved positions, suggesting that they might be deleterious. The MD analyses indicate that the mutations P206S, R303W, and R441H affect TPH2 flexibility and essential mobility at the catalytic and oligomerization domains. The variants P206S, R303W, and R441H also exhibited alterations in dimer binding affinity and stability throughout the simulations. Thus, these mutations may impair TPH2 functional interactions and, consequently, its function, leading to the development of PD. Furthermore, we developed a database, SNPMOL (http://www.snpmol.org/), containing the results presented in this paper. Understanding the effects of TPH2 mutations on protein structure and function may lead to improvements in existing treatments for PD and facilitate the design of further experiments.

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

Cited by 38 publications

References 65 publications

Complex formation dynamics of native and mutated pyrin's B30.2 domain with caspase‐1

Complex formation dynamics of native and mutated pyrin's B30.2 domain with caspase‐1

In silico analysis and molecular dynamics simulation of human superoxide dismutase 3 (SOD3) genetic variants

In silico analysis of the tryptophan hydroxylase 2 (TPH2) protein variants related to psychiatric disorders

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