Structural Insights into Hearing Loss Genetics from Polarizable Protein Repacking

Tollefson, Mallory R.; Litman, Jacob M.; Qi, Guowei; O’Connell, C. E.; Wipfler, M. J.; Marini, Robert J.; Bernabe, H.V.; Tollefson, William T.A.; Braun, Terry A.; Casavant, Thomas L.; Smith, Richard J.H.; Schnieders, Michael J.

doi:10.1016/j.bpj.2019.06.030

Cited by 14 publications

(23 citation statements)

References 51 publications

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“…Additional computational methods were used to predict the structural effects of the DNM on one of the most reported cleft candidate gene products. Starting from the predicted protein structures generated by AlphaFold2, we locally optimized the structure to relax its backbone torsions and performed sidechain optimization (i.e., sidechain repacking ) to find the most favorable position for each sidechain and improve MolProbity scores 69 . Both optimizations were done with the AMOEBA polarizable force field 70 , 71 .…”

Section: Methodsmentioning

confidence: 99%

Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate

Awotoye

Mossey

Hetmanski

et al. 2022

Sci Rep

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The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact protein-altering DNMs that contribute to the risk of nsCL/P, we conducted whole-genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs some of which are based on available evidence, contribute to the risk of nsCL/P. These include novel protein-truncating DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Many of these protein-altering DNMs were predicted to be pathogenic. Analysis using mouse transcriptomics data showed that some of these genes are expressed during the development of primary and secondary palate. Gene-set enrichment analysis of the protein-altering DNMs identified palatal development and neural crest migration among the few processes that were significantly enriched. These processes are directly involved in the etiopathogenesis of clefting. The analysis of the coding sequence in the WGS data provides more evidence of the opportunity for novel findings in the African genome.

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Section: Methodsmentioning

confidence: 99%

Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate

Awotoye

Mossey

Hetmanski

et al. 2022

Sci Rep

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“…MolProbity performed contact analysis between all atoms, Ramachandran plot, and rotamer distribution (side chain) [36]. A lower MolProbity value indicates a higher structural quality [37].…”

Section: Ipbcc08610 God Structurementioning

confidence: 99%

Molecular Docking Study of IPBCC.08.610 Glucose Oxidase Mutant for Increasing Gluconic Acid Production

et al. 2022

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Glucose oxidase (GOD) is an oxidoreductase enzyme that catalyzes the oxidation of glucose to gluconolactone and hydrogen peroxide. Then, gluconolactone will be hydrolyzed to gluconic acid. The wide application of gluconic acid in various industries has increased production demand. However, glucose concentrations higher than 40% (w/w) inhibited the conversion of glucose to gluconic acid due to a decrease in the oxygen solubility concentration at pH 6, 30℃, and 1 bar pressure. Therefore, decreasing the value of Km is predicted to reduce saturation and enhance gluconic acid production. This study aimed to analyze the interaction between the IPBCC.08.610 GOD mutant with β-D-Glucose in improving gluconic acid production by decreasing the Km value. Mutations were performed in silico using Chimera and then docked using AutoDock Vina. The mutations resulted in distinct ligand poses in the binding pocket, different -OH conformations of the ligands, and changes in the T554M/D578P mutant’s hydrophobicity index (554 mutated from threonine to methionine, and 578 mutated from aspartate to proline), and decreased ΔG and Km values in the H559D mutant (559 mutated from histidine to aspartate), D578P and T554M/D578P. This decrease might strengthen the ligand-receptor interaction, increasing gluconic acid production. The H559D was the best mutant to increase production based on the ΔG, Km value, and stability due to the addition of hydrogen bonds.

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“…Initial optimization was performed with a root mean square (RMS) convergence criterion of 0.8 kcal/mol/Å. Many-body energy expansions were applied to the refined structures using the AMOEBA forcefield to optimize side-chain placement and improve MolProbity scores [81]. The optimized structures were locally optimized again with an RMS convergence criterion of 0.1 kcal/mol/Å to finalize backbone torsions with the optimized sidechain placement.…”

Section: Deep Learning Prediction Of Full-length Laminmentioning

confidence: 99%

In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies

Hinz

Walker

Xiong

et al. 2021

IJMS

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Mutations in the LMNA gene cause diseases called laminopathies. LMNA encodes lamins A and C, intermediate filaments with multiple roles at the nuclear envelope. LMNA mutations are frequently single base changes that cause diverse disease phenotypes affecting muscles, nerves, and fat. Disease-associated amino acid substitutions were mapped in silico onto three-dimensional structures of lamin A/C, revealing no apparent genotype–phenotype connections. In silico analyses revealed that seven of nine predicted partner protein binding pockets in the Ig-like fold domain correspond to sites of disease-associated amino acid substitutions. Different amino acid substitutions at the same position within lamin A/C cause distinct diseases, raising the question of whether the nature of the amino acid replacement or genetic background differences contribute to disease phenotypes. Substitutions at R249 in the rod domain cause muscular dystrophies with varying severity. To address this variability, we modeled R249Q and R249W in Drosophila Lamin C, an orthologue of LMNA. Larval body wall muscles expressing mutant Lamin C caused abnormal nuclear morphology and premature death. When expressed in indirect flight muscles, R249W caused a greater number of adults with wing posturing defects than R249Q, consistent with observations that R249W and R249Q cause distinct muscular dystrophies, with R249W more severe. In this case, the nature of the amino acid replacement appears to dictate muscle disease severity. Together, our findings illustrate the utility of Drosophila for predicting muscle disease severity and pathogenicity of variants of unknown significance.

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Structural Insights into Hearing Loss Genetics from Polarizable Protein Repacking

Cited by 14 publications

References 51 publications

Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate

Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate

Molecular Docking Study of IPBCC.08.610 Glucose Oxidase Mutant for Increasing Gluconic Acid Production

In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies

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