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Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics–Molecular Mechanics Framework

A whole-exome capture and next-generation sequencing was applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, and severe cognitive deficit, and without any identifiable Syndromic pattern, and to her parents, we disclo...

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Autores principales: López-Rivera, Juan Javier, Rodríguez-Salazar, Luna, Soto-Ospina, Alejandro, Estrada-Serrato, Carlos, Serrano, David, Chaparro-Solano, Henry Mauricio, Londoño, Olga, Rueda, Paula A., Ardila, Geraldine, Villegas-Lanau, Andrés, Godoy-Corredor, Marcela, Cuartas, Mauricio, Vélez, Jorge I., Vidal, Oscar M., Isaza-Ruget, Mario A., Arcos-Burgos, Mauricio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313109/
https://www.ncbi.nlm.nih.gov/pubmed/35884678
http://dx.doi.org/10.3390/brainsci12070871
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author López-Rivera, Juan Javier
Rodríguez-Salazar, Luna
Soto-Ospina, Alejandro
Estrada-Serrato, Carlos
Serrano, David
Chaparro-Solano, Henry Mauricio
Londoño, Olga
Rueda, Paula A.
Ardila, Geraldine
Villegas-Lanau, Andrés
Godoy-Corredor, Marcela
Cuartas, Mauricio
Vélez, Jorge I.
Vidal, Oscar M.
Isaza-Ruget, Mario A.
Arcos-Burgos, Mauricio
author_facet López-Rivera, Juan Javier
Rodríguez-Salazar, Luna
Soto-Ospina, Alejandro
Estrada-Serrato, Carlos
Serrano, David
Chaparro-Solano, Henry Mauricio
Londoño, Olga
Rueda, Paula A.
Ardila, Geraldine
Villegas-Lanau, Andrés
Godoy-Corredor, Marcela
Cuartas, Mauricio
Vélez, Jorge I.
Vidal, Oscar M.
Isaza-Ruget, Mario A.
Arcos-Burgos, Mauricio
author_sort López-Rivera, Juan Javier
collection PubMed
description A whole-exome capture and next-generation sequencing was applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, and severe cognitive deficit, and without any identifiable Syndromic pattern, and to her parents, we disclosed a de novo heterozygous pathogenic mutation, c.697_699del p.Phe233del (rs786204835)(ACMG classification PS2, PM1, PM2, PP5), harbored in the PURA gene (MIM*600473) (5q31.3), associated with Autosomal Dominant Mental Retardation 31 (MIM # 616158). We used the significant improvement in the accuracy of protein structure prediction recently implemented in AlphaFold that incorporates novel neural network architectures and training procedures based on the evolutionary, physical, and geometric constraints of protein structures. The wild-type (WT) sequence and the mutated sequence, missing the Phe233, were reconstructed. The predicted local Distance Difference Test (lDDT) for the PURAwt and the PURA–Phe233del showed that the occurrence of the Phe233del affects between 220–320 amino acids. The distortion in the PURA structural conformation in the ~5 Å surrounding area after the p.Phe233del produces a conspicuous disruption of the repeat III, where the DNA and RNA helix unwinding capability occurs. PURA Protein–DNA docking corroborated these results in an in silico analysis that showed a loss of the contact of the PURA–Phe233del III repeat domain model with the DNA. Together, (i) the energetic and stereochemical, (ii) the hydropathic indexes and polarity surfaces, and (iii) the hybrid Quantum Mechanics–Molecular Mechanics (QM–MM) analyses of the PURA molecular models demarcate, at the atomic resolution, the specific surrounding region affected by these mutations and pave the way for future cell-based functional analysis. To the best of our knowledge, this is the first report of a de novo mutation underpinning a PURA syndrome in a Latin American patient and highlights the importance of predicting the molecular effects in protein structure using artificial intelligence algorithms and molecular and atomic resolution stereochemical analyses.
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spelling pubmed-93131092022-07-26 Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics–Molecular Mechanics Framework López-Rivera, Juan Javier Rodríguez-Salazar, Luna Soto-Ospina, Alejandro Estrada-Serrato, Carlos Serrano, David Chaparro-Solano, Henry Mauricio Londoño, Olga Rueda, Paula A. Ardila, Geraldine Villegas-Lanau, Andrés Godoy-Corredor, Marcela Cuartas, Mauricio Vélez, Jorge I. Vidal, Oscar M. Isaza-Ruget, Mario A. Arcos-Burgos, Mauricio Brain Sci Article A whole-exome capture and next-generation sequencing was applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, and severe cognitive deficit, and without any identifiable Syndromic pattern, and to her parents, we disclosed a de novo heterozygous pathogenic mutation, c.697_699del p.Phe233del (rs786204835)(ACMG classification PS2, PM1, PM2, PP5), harbored in the PURA gene (MIM*600473) (5q31.3), associated with Autosomal Dominant Mental Retardation 31 (MIM # 616158). We used the significant improvement in the accuracy of protein structure prediction recently implemented in AlphaFold that incorporates novel neural network architectures and training procedures based on the evolutionary, physical, and geometric constraints of protein structures. The wild-type (WT) sequence and the mutated sequence, missing the Phe233, were reconstructed. The predicted local Distance Difference Test (lDDT) for the PURAwt and the PURA–Phe233del showed that the occurrence of the Phe233del affects between 220–320 amino acids. The distortion in the PURA structural conformation in the ~5 Å surrounding area after the p.Phe233del produces a conspicuous disruption of the repeat III, where the DNA and RNA helix unwinding capability occurs. PURA Protein–DNA docking corroborated these results in an in silico analysis that showed a loss of the contact of the PURA–Phe233del III repeat domain model with the DNA. Together, (i) the energetic and stereochemical, (ii) the hydropathic indexes and polarity surfaces, and (iii) the hybrid Quantum Mechanics–Molecular Mechanics (QM–MM) analyses of the PURA molecular models demarcate, at the atomic resolution, the specific surrounding region affected by these mutations and pave the way for future cell-based functional analysis. To the best of our knowledge, this is the first report of a de novo mutation underpinning a PURA syndrome in a Latin American patient and highlights the importance of predicting the molecular effects in protein structure using artificial intelligence algorithms and molecular and atomic resolution stereochemical analyses. MDPI 2022-06-30 /pmc/articles/PMC9313109/ /pubmed/35884678 http://dx.doi.org/10.3390/brainsci12070871 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
López-Rivera, Juan Javier
Rodríguez-Salazar, Luna
Soto-Ospina, Alejandro
Estrada-Serrato, Carlos
Serrano, David
Chaparro-Solano, Henry Mauricio
Londoño, Olga
Rueda, Paula A.
Ardila, Geraldine
Villegas-Lanau, Andrés
Godoy-Corredor, Marcela
Cuartas, Mauricio
Vélez, Jorge I.
Vidal, Oscar M.
Isaza-Ruget, Mario A.
Arcos-Burgos, Mauricio
Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics–Molecular Mechanics Framework
title Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics–Molecular Mechanics Framework
title_full Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics–Molecular Mechanics Framework
title_fullStr Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics–Molecular Mechanics Framework
title_full_unstemmed Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics–Molecular Mechanics Framework
title_short Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics–Molecular Mechanics Framework
title_sort structural protein effects underpinning cognitive developmental delay of the pura p.phe233del mutation modelled by artificial intelligence and the hybrid quantum mechanics–molecular mechanics framework
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313109/
https://www.ncbi.nlm.nih.gov/pubmed/35884678
http://dx.doi.org/10.3390/brainsci12070871
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