scholarly journals Obesity associated with a novel mitochondrial tRNACys 5802A>G mutation in a Chinese family

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Jinling Wang ◽  
Ningning Zhao ◽  
Xiaoting Mao ◽  
Feilong Meng ◽  
Ke Huang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Profiling ◽  
Pedigree Analysis ◽  
Dynamics Simulation ◽  
Chinese Family ◽  
Wild Type ◽  
Clinical Genetic ◽  
Single Generation ◽  
Codon Recognition ◽  
Stem Position

Abstract A Chinese family with matrilineally inherited obesity was assessed and its clinical, genetic, and molecular profiling was conducted. Obesity was observed in matrilineal relatives (3 out of 7) of a single generation (of 3 alive generations) in this family. On pedigree analysis and sequencing of their mitochondrial DNA (mtDNA), a novel homoplasmic mutation of the mitochondrial tRNACys gene (5802A>G) was identified in these individuals. This mutation correlated with a destabilized conserved base pair in this tRNA anticodon stem. Position 30 is known to be crucial for carrying out effective codon recognition and stability of tRNA. In accordance with the importance of this conserved site, we observed that the predicted structure of tRNACys with the mutation was noticeably remodeled in a molecular dynamics simulation when compared with the isoform of the wild-type. All other 46 mutations observed in the individual’s mtDNA were known variants belonging to haplogroup D4. Thus, this is the first report that provides evidence of the association between a mutation in tRNA and an enhanced risk of maternally transmissible obesity, offering more insights into obesity and its underlying nature.

scholarly journals Obesity is potentially associated with a novel mitochondrial tRNAGly 10029A>G mutation in a Chinese family

2019 ◽  
Author(s):  
Jinling Wang ◽  
Ningning Zhao ◽  
Xiaoting Mao ◽  
Feilong Meng ◽  
Ke Huang ◽  
...  
Keyword(s):  
Molecular Profiling ◽  
Pedigree Analysis ◽  
Elevated Risk ◽  
Dynamics Simulation ◽  
Chinese Family ◽  
Obesity Risk ◽  
Wild Type ◽  
Clinical Genetic ◽  
Codon Recognition ◽  
Public Health Challenges

Abstract Background Obesity is one of the most prominent public health challenges globally. Mutations in mitochondrial genes can similarly lead to the onset of childhood obesity remains unclear. Methods we conducted a clinical, genetic, and molecular profiling of a Han Chinese family with evident of matrilineally-inherited obesity. Obesity was evident in 2/6 matrilineal relatives in a single generation of this family (of 3 available generations). When the mitochondrial DNA of these individuals was sequences and a pedigree analysis was performed. Results We were able to identify a novel homoplasmic mutation of the mitochondrial tRNAGly gene (10029A>G) in these individuals. This mutation was linked to destabilization of a conserved base pair in the anticodon of this tRNA. This position (position 43) is known to be important for mediating effective codon recognition and tRNA stability. Consistent with the importance of this conserved site, we found that the predicted structure of a tRNAGly structure bearing a 10029A>G mutation was markedly altered in a molecular dynamics simulation relative to the wild-type isoform. All other mutations identified in the mtDNA of this individual were known variants associated with Asian haplogroup D4. Conclusion Our report provides novel evidence of a link between a tRNA mutation and an elevated risk of maternally-transmissible obesity risk, offering potentially novel insights into the underlying nature of obesity.

scholarly journals 1P255 Molecular Dynamics Simulation of the Wild-Type and Mutated LOV2 Domains

2005 ◽  
Vol 45 (supplement) ◽  
pp. S95
Author(s):  
M. Nabeno ◽  
N. Kamiya ◽  
J. Higo ◽  
S. Tokutomi ◽  
M. Sakurai
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Dynamics Simulation ◽  
Wild Type

Quantum Mechanical/Molecular Mechanical Molecular Dynamics Simulation of Wild-Type and Seven Mutants ofCpNagJ in Complex with PUGNAc

2010 ◽  
Vol 114 (20) ◽  
pp. 7029-7036 ◽  
Author(s):  
Jeronimo Lameira ◽  
Cláudio Nahum Alves ◽  
Vicent Moliner ◽  
Sergio Martí ◽  
Raquel Castillo ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Dynamics Simulation ◽  
Quantum Mechanical ◽  
Wild Type

scholarly journals Construction of Novel Aspartokinase Mutant A380I and Its Characterization by Molecular Dynamics Simulation

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3379 ◽  
Author(s):  
Caijing Han ◽  
Li Fang ◽  
Chunlei Liu ◽  
Yunna Gao ◽  
Weihong Min
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
High Throughput Screening ◽  
Model Comparison ◽  
Site Directed Mutagenesis ◽  
Dynamics Simulation ◽  
Wild Type ◽  
Open Conformation ◽  
Simulation Results ◽  
Optimal Ph

In this study, a novel monomer aspartokinase (AK) from Corynebacterium pekinense was identified, and its monomer model was constructed. Site 380 was identified by homologous sequencing and monomer model comparison as the key site which was conserved and located around the binding site of the inhibitor Lys. Furthermore, the mutant A380I with enzyme activity 11.32-fold higher than wild type AK (WT-AK), was obtained by site-directed mutagenesis and high throughput screening. In the mutant A380I, the optimal temperature was raised from 26 °C (WT-AK) to 28 °C, the optimal pH remained unchanged at 8.0, and the half-life was prolonged from 4.5 h (WT-AK) to 6.0 h, indicating enhanced thermal stability. The inhibition of A380I was weakened at various inhibitor concentrations and even activated at certain inhibitor concentrations (10 mM of Lys, 5 mM or 10 mM of Lys + Thr, 10 mM of Lys + Met, 5 mM of Lys + Thr + Met). Molecular dynamics simulation results indicated that the occupancy rate of hydrogen bond between A380I and ATP was enhanced, the effect of Lys (inhibitor) on the protein was weakened, and the angle between Ser281-Tyre358 and Asp359-Gly427 was increased after mutation, leading to an open conformation (R-state) that favored the binding of substrate.

scholarly journals Molecular Dynamics Simulations of Wild Type and Mutants of SAPAP in Complexed with Shank3

2019 ◽  
Vol 20 (1) ◽  
pp. 224 ◽  
Author(s):  
Lianhua Piao ◽  
Zhou Chen ◽  
Qiuye Li ◽  
Ranran Liu ◽  
Wei Song ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Specific Binding ◽  
Neurological Diseases ◽  
Pdz Domain ◽  
Dynamics Simulation ◽  
Binding Motif ◽  
Wild Type ◽  
Set Up ◽  
Dynamics Simulations ◽  
High Flexibility

Specific interactions between scaffold protein SH3 and multiple ankyrin repeat domains protein 3 (Shank3) and synapse-associated protein 90/postsynaptic density-95–associated protein (SAPAP) are essential for excitatory synapse development and plasticity. In a bunch of human neurological diseases, mutations on Shank3 or SAPAP are detected. To investigate the dynamical and thermodynamic properties of the specific binding between the N-terminal extended PDZ (Post-synaptic density-95/Discs large/Zonaoccludens-1) domain (N-PDZ) of Shank3 and the extended PDZ binding motif (E-PBM) of SAPAP, molecular dynamics simulation approaches were used to study the complex of N-PDZ with wild type and mutated E-PBM peptides. To compare with the experimental data, 974QTRL977 and 966IEIYI970 of E-PBM peptide were mutated to prolines to obtain the M4P and M5P system, respectively. Conformational analysis shows that the canonical PDZ domain is stable while the βN extension presents high flexibility in all systems, especially for M5P. The high flexibility of βN extension seems to set up a barrier for the non-specific binding in this area and provide the basis for specific molecular recognition between Shank3 and SAPAP. The wild type E-PBM tightly binds to N-PDZ during the simulation while loss of binding is observed in different segments of the mutated E-PBM peptides. Energy decomposition and hydrogen bonds analysis show that M4P mutations only disrupt the interactions with canonical PDZ domain, but the interactions with βN1′ remain. In M5P system, although the interactions with βN1′ are abolished, the binding between peptide and the canonical PDZ domain is not affected. The results indicate that the interactions in the two-binding site, the canonical PDZ domain and the βN1′ extension, contribute to the binding between E-PBM and N-PDZ independently. The binding free energies calculated by MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) are in agreement with the experimental binding affinities. Most of the residues on E-PBM contribute considerably favorable energies to the binding except A963 and D964 in the N-terminal. The study provides information to understand the molecular basis of specific binding between Shank3 and SAPAP, as well as clues for design of peptide inhibitors.

scholarly journals Molecular Dynamics Study of Insulin Mutants

2021 ◽  
Keyword(s):  
Molecular Dynamics ◽  
Protein Structure ◽  
Secondary Structure ◽  
Root Mean Square ◽  
Human Insulin ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Mean Square ◽  
Wild Type ◽  
Secondary Structure Content

Human insulin, a small protein hormone consisting of A-chain (21 residues) and B-chain (30 residues) linked by three disulfide bonds, is crucial for controlling the hyperglycemia in type I diabetes. In the present work molecular dynamics simulation (MD) with human insulin and its mutants was used to assess the influence of 10 point mutations (HisA8, ValA10, AspB10, GlnB17, AlaB17, GlnB18, AspB25, ThrB26, GluB27, AspB28), 6 double mutations (GluA13+GluB10, SerA13+GluB27, GluB1+GluB27, SerB2+AspB10, AspB9+GluB27, GluB16+GluB27) and one triple mutation (GluA15+AspA18+AspB3) in the protein sequence on the structure and dynamics of human insulin. A series of thermal unfolding MD simulations with wild type (WT) human insulin and its mutants was performed at 400 K with GROMACS software (version 5.1) using the CHARMM36m force field. The MD results have been analyzed in terms of the parameters characterizing both the global and local protein structure, such as the backbone root mean-square deviation, gyration radius, solvent accessible surface area, the root mean-square fluctuations and the secondary structure content. The MD simulation data showed that depending on time evolution of integral characteristics, the examined mutants can be tentatively divided into three groups: 1) the mutants HisA8, ValA10, AlaB17, AspB25, ThrB26, GluB27, GluA13+GluB10, GluB1+GluB27 and GluB16+GluB27, which exert stabilizing effect on the protein structure in comparison with wild type insulin; 2) the mutants GlnB17, AspB10, SerB2+AspB10 and GluA15+AspA18+AspB3 that did not significantly affect the dynamical properties of human insulin with a minimal stabilizing impact; 3) the mutants AspB28, AspB9+GluB27 and SerA13+GluB27, GlnB18, destabilizing the protein structure. Analysis of the secondary structure content provided evidence for the influence of AspB28, AspB9+GluB27 and SerA13+GluB27, GlnB18 on the insulin unfolding. Our MD results indicate that the replacement of superficial nonpolar residues in the insulin structure by hydrophilic ones gives rise to the increase in protein stability in comparison with the wild type protein.

Screening of natural compounds against SOD1 as a therapeutic target for Amyotrophic lateral sclerosis

2021 ◽  
Vol 19 ◽  
Author(s):  
Sonu Pahal ◽  
Amit Chaudhary ◽  
Sangeeta Singh
Keyword(s):  
Molecular Dynamics ◽  
Amyotrophic Lateral Sclerosis ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Virtual Screening ◽  
Dynamics Simulation ◽  
Pharmacokinetic Parameters ◽  
Wild Type ◽  
Potential Inhibitors ◽  
Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is an uncommon and progressive neurological illness that predominantly includes the neurons liable for voluntary muscular activities. Starting from weakness or stiffness in muscles, this gradually exploits the strength and ability to speak, eat, move and even breathe. Its exact mechanism is still not clear, but mutations in the SOD1 gene have been reported to cause ALS, and some studies also found involvement of SOD1 overexpression in the pathogenesis of ALS. As of now, there is no remedy available for its cure. Objective: To identify the potential inhibitors for wild type 1HL5, l113T mutant, and A4V mutant of SOD1 (Superoxide Dismutase 1) protein. Methods: In this study, in silico approaches like virtual screening, molecular docking, pharmacokinetic parameters study, and molecular dynamics simulation were used to identify the best potential inhibitors against wild type and mutant SOD1 protein. Methods: In this study, in silico approaches like virtual screening, molecular docking, pharmacokinetic parameters study, and molecular dynamics simulation were used to identify the best potential inhibitors against wild type and mutant SOD1 protein. Results: On the basis of binding affinity and binding energy, the top three compounds ZINC000095486263, ZINC000095485989, and ZINC000028462577, were observed as the best compounds. In the case of 1HL5, ZINC000095486263 had the highest binding affinity with docking score -10.62 Kcal/mol, 1UXM with ZINC000095485989 had the highest docking score -12.03 Kcal/mol, and 4A7V with ZINC000028462577 was found -11.72 Kcal/mol. Further, Molecular Dynamic simulations (MDS) results showed that the ZINC000095486263, ZINC000095485989, and ZINC000095485956 compounds were formed a stable complex with 1HL5, 1UXM, and 4A7V, respectively Conclusions: : After analyzing the results, we hereby conclude that naturals compounds such as ZINC000095486263, ZINC000095485989, and ZINC000095485956 could be used as a potential inhibitor of 1HL5, 1UXM, and 4A7V, respectively, for ALS treatment and could be used as a drug. Further, In vivo/vitro study of these compounds could be a future direction in the field of drug discovery.

scholarly journals Design of an adenosine phosphorylase by active-site modification of murine purine nucleoside phosphorylase: Enzyme kinetics and molecular dynamics simulation of Asn-243 and Lys-244 substitutions of purine nucleoside phosphorylase

1999 ◽  
Vol 344 (2) ◽  
pp. 585-592 ◽  
Author(s):  
Jason T. MAYNES ◽  
W.-S. YAM ◽  
Jack P. JENUTH ◽  
R. Gang YUAN ◽  
Steven A. LITSTER ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Purine Nucleoside Phosphorylase ◽  
Fold Increase ◽  
Purine Nucleoside ◽  
Dynamics Simulation ◽  
Amino Group ◽  
Wild Type ◽  
Nucleoside Phosphorylase ◽  
Purine Ring

Our objective was to alter the substrate specificity of purine nucleoside phosphorylase such that it would catalyse the phosphorolysis of 6-aminopurine nucleosides. We modified both Asn-243 and Lys-244 in order to promote the acceptance of the C6-amino group of adenosine. The Asn-243-Asp substitution resulted in an 8-fold increase in Km for inosine from 58 to 484 μM and a 1000-fold decrease in kcat/Km. The Asn-243-Asp construct catalysed the phosphorolysis of adenosine with a Km of 45 μM and a kcat/Km 8-fold that with inosine. The Lys-244-Gln construct showed only marginal reduction in kcat/Km, 83% of wild type, but had no activity with adenosine. The Asn-243-Asp;Lys-244-Gln construct had a 14-fold increase in Km with inosine and 7-fold decrease in kcat/Km as compared to wild type. This double substitution catalysed the phosphorolysis of adenosine with a Km of 42 μM and a kcat/Km twice that of the single Asn-243-Asp substitution. Molecular dynamics simulation of the engineered proteins with adenine as substrate revealed favourable hydrogen bond distances between N7 of the purine ring and the Asp-243 carboxylate at 2.93 and 2.88 Å, for Asn-243-Asp and the Asn-243-Asp;Lys-244-Gln constructs respectively. Simulation also supported a favourable hydrogen bond distance between the purine C6-amino group and Asp-243 at 2.83 and 2.88 Å for each construct respectively. The Asn-243-Thr substitution did not yield activity with adenosine and simulation gave unfavourable hydrogen bond distances between Thr-243 and both the C6-amino group and N7 of the purine ring. The substitutions were not in the region of phosphate binding and the apparent S0.5 for phosphate with wild type and the Asn-243-Asp enzymes were 1.35±0.01 and 1.84±0.06 mM, respectively. Both proteins exhibited positive co-operativity with phosphate giving Hill coefficients of 7.9 and 3.8 respectively.

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