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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

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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·2022·Brain Sciences
DOI 10.3390/brainsci12070871PMC PMC9313109

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Abstract

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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Figures

Figure 1 (a) De novo heterozygous mutation found in the proband, c.697_699del (p.Phe233del), NM_005859.5, PURA (MIM*600473), located at Chr5:139,494,453-139,494,455 (rs786204835). This deletion causes the loss of Phenylalanine at residue 233 of the protein (in-frame), codon located from position 697 to 699 of the cDNA. (b) β-sheet composition with three Phenylalanine expansions: Phe231 (red), Phe232 (green), and Phe 233 (magenta). (c) Phe233 shows its hydrogens in a #D conformation (magenta arrow). (d) Phe233 polar contact measurements are less than 4 Å (magenta arrow).
Figure 1 (a) De novo heterozygous mutation found in the proband, c.697_699del (p.Phe233del), NM_005859.5, PURA (MIM*600473), located at Chr5:139,494,453-139,494,455 (rs786204835). This deletion causes the loss of Phenylalanine at residue 233 of the protein (in-frame), codon located from position 697 to 699 of the cDNA. (b) β-sheet composition with three Phenylalanine expansions: Phe231 (red), Phe232 (green), and Phe 233 (magenta). (c) Phe233 shows its hydrogens in a #D conformation (magenta arrow). (d) Phe233 polar contact measurements are less than 4 Å (magenta arrow).CC BY · PubMed Central
Figure 2 (a) PURAwt AlphaFold modeling showing the three principal purine-rich (PUR) elements (in white). Magenta arrows show the DNA docking site regions forming a spanner head that will interact with the DNA. (b) Zoom of the protein–DNA docking site with three principal residues in contact with the DNA molecule (c-MYC promoter region), THR 252, TYR 253, and ARG 254. (c) Zoom and 180-degree rotation to visualize the opposite protein–DNA docking site with its three principal residues in contact with the DNA molecule (c-MYC promoter region), VAL 149, GLU 151, and LYS 154.
Figure 2 (a) PURAwt AlphaFold modeling showing the three principal purine-rich (PUR) elements (in white). Magenta arrows show the DNA docking site regions forming a spanner head that will interact with the DNA. (b) Zoom of the protein–DNA docking site with three principal residues in contact with the DNA molecule (c-MYC promoter region), THR 252, TYR 253, and ARG 254. (c) Zoom and 180-degree rotation to visualize the opposite protein–DNA docking site with its three principal residues in contact with the DNA molecule (c-MYC promoter region), VAL 149, GLU 151, and LYS 154.CC BY · PubMed Central
Figure 3 The PURA–DNA comparative analyses show that DNA docking damages PURA Protein–DNA docking. (a) In silico analysis by HDOCK shows 10 top models between PURA-WT AlphaFold and previously reported DNA promoter regions of the c-Myc. (b) HDOCK docking analysis between AlpahFold predicted PURA–Phe233del protein and the c-Myc DNA promoter regions.
Figure 3 The PURA–DNA comparative analyses show that DNA docking damages PURA Protein–DNA docking. (a) In silico analysis by HDOCK shows 10 top models between PURA-WT AlphaFold and previously reported DNA promoter regions of the c-Myc. (b) HDOCK docking analysis between AlpahFold predicted PURA–Phe233del protein and the c-Myc DNA promoter regions.CC BY · PubMed Central
Figure 4 Hydrophobicity analysis (Molecular Lipophilicity Potential, MLP maps) of the (a) PURAwt, and (b) PURAPhe233del system. The analysis shows that in the wild type variant, the Phe 233 is harbored in a golden region (hydrophobic), implicating that it plays a significant role in the 3D arrangement, while the hydrophobicity changes once the deletion occurs. This is also appreciated in (c), which depicts the hydrophobicity index plot zooming in on the 233-amino-acid region (see text).
Figure 4 Hydrophobicity analysis (Molecular Lipophilicity Potential, MLP maps) of the (a) PURAwt, and (b) PURAPhe233del system. The analysis shows that in the wild type variant, the Phe 233 is harbored in a golden region (hydrophobic), implicating that it plays a significant role in the 3D arrangement, while the hydrophobicity changes once the deletion occurs. This is also appreciated in (c), which depicts the hydrophobicity index plot zooming in on the 233-amino-acid region (see text).CC BY · PubMed Central
Figure 5 Functional comparison of the connective and electronic structures for the QM/MM simulation of PURAwt and PURA–Phe233del. (a) For PURAwt, the angle between amino acids F232-F233 was 37.57°, while for F233-D234, the bond angle distancing the CH2 carbons constituting the side chain by 7.215 Å was 113.84° (reference distance of the amino acids in the β-sheets). (b) For PURA–Phe233del, the bond angle between F231-F232 is 35.51°, and the bond angle between F232-D233 changes to 112.47°, indicating that the binding distance for the reference structure decreases to 6.103 Å, which affects the accessible area of the structure. (c) Electrostatic potential maps of the PURAwt β-sheets involved. The area and volume values for the electronic region in the region undergoing variation were 3032.37 Å2 and 2930.94 Å3, respectively. (d) Electrostatic potential maps of the PURA–Phe233del β-sheets. The area and volume values for the electronic region in the region undergoing variation change to 2852.30 Å2 and 2773.77 Å3, respectively, which is in agreement with the loss of enough electronic topology contributed by the Phe233 amino acid and its aromaticity.
Figure 5 Functional comparison of the connective and electronic structures for the QM/MM simulation of PURAwt and PURA–Phe233del. (a) For PURAwt, the angle between amino acids F232-F233 was 37.57°, while for F233-D234, the bond angle distancing the CH2 carbons constituting the side chain by 7.215 Å was 113.84° (reference distance of the amino acids in the β-sheets). (b) For PURA–Phe233del, the bond angle between F231-F232 is 35.51°, and the bond angle between F232-D233 changes to 112.47°, indicating that the binding distance for the reference structure decreases to 6.103 Å, which affects the accessible area of the structure. (c) Electrostatic potential maps of the PURAwt β-sheets involved. The area and volume values for the electronic region in the region undergoing variation were 3032.37 Å2 and 2930.94 Å3, respectively. (d) Electrostatic potential maps of the PURA–Phe233del β-sheets. The area and volume values for the electronic region in the region undergoing variation change to 2852.30 Å2 and 2773.77 Å3, respectively, which is in agreement with the loss of enough electronic topology contributed by the Phe233 amino acid and its aromaticity.CC BY · PubMed Central
Figure 6 (a) Predicted local Distance Difference Test (lDDT) for the PURA WT and (b) PURA–Phe233del-predicted structure deletion per amino acid using five different models via AlpahFold2. Models show that the occurrence of the Phe233del affects between 220–320 amino acids (red arrow). (c) A 3D reconstruction of the transcriptional activator protein Pur-alpha (PURA; Uniprot: Q00577) from the WT sequence using AlphaFold, focusing on the surrounding area of the Phe233 amino acid (in magenta; magenta arrow). (d) A 3D reconstruction of the PURA–Phe233del. Note the distortion (61.3 Å vs. 64.3 Å) in PURA structural conformation after the p.Phe233del occurs.
Figure 6 (a) Predicted local Distance Difference Test (lDDT) for the PURA WT and (b) PURA–Phe233del-predicted structure deletion per amino acid using five different models via AlpahFold2. Models show that the occurrence of the Phe233del affects between 220–320 amino acids (red arrow). (c) A 3D reconstruction of the transcriptional activator protein Pur-alpha (PURA; Uniprot: Q00577) from the WT sequence using AlphaFold, focusing on the surrounding area of the Phe233 amino acid (in magenta; magenta arrow). (d) A 3D reconstruction of the PURA–Phe233del. Note the distortion (61.3 Å vs. 64.3 Å) in PURA structural conformation after the p.Phe233del occurs.CC BY · PubMed Central
Figure 7 PURA–Phe233del disrupts DNA biding. (a) A molecular view of PURA Protein–DNA docking analysis showing three different HDOCK models between PURAwt AlphaFold and the c-Myc DNA promoter region. Magenta arrows indicate disruption of specific docking sites (in white; magenta arrows). (b) HDOCK docking analysis shows the c-Myc DNA binding disruption caused by the AlpahFold2 predicted PURA–Phe233del protein.
Figure 7 PURA–Phe233del disrupts DNA biding. (a) A molecular view of PURA Protein–DNA docking analysis showing three different HDOCK models between PURAwt AlphaFold and the c-Myc DNA promoter region. Magenta arrows indicate disruption of specific docking sites (in white; magenta arrows). (b) HDOCK docking analysis shows the c-Myc DNA binding disruption caused by the AlpahFold2 predicted PURA–Phe233del protein.CC BY · PubMed Central

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Metadata

Authors
López-Rivera, J. J., Rodríguez-Salazar, L., Soto-Ospina, A., Estrada-Serrato, C., Serrano, D., Chaparro-Solano, H. M., Londoño, O., Rueda, P. A., Ardila, G., Villegas-Lanau, A., Godoy-Corredor, M., Cuartas, M., Vélez, J. I., Vidal, O. M., Isaza-Ruget, M. A., & Arcos-Burgos, M.
Affiliations
  • INPAC Research Group, Fundación Universitaria Sanitas, Bogotá 111321, Colombia
  • Grupo de Bioinformática, Laboratorio de Clínica Colsanitas, Bogotá 110221, Colombia
  • Universidad de Antioquia (CO)
  • Grupo de Genética Médica, Clínica Universitaria Colombia y Clínica Pediátrica Colsanitas, Bogotá 111321, Colombia
  • Genética Molecular (GenMol), Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín 050012, Colombia
  • Laboratorio Clínico y de Patología, Clínica Colsanitas, Bogotá 110221, Colombia
  • Grupo de Investigación Estudios en Psicología, Departamento de Psicología, Escuela de Humanidades, Universidad EAFIT, Medellín 050022, Colombia
  • Universidad del Norte, Barranquilla 080001, Colombia
  • Universidad del Norte (CO)
  • Fundación Universitaria Sanitas (CO)
  • Grupo de Investigación en Psiquiatría (GIPSI), Departamento de Psiquiatría, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, Medellín 050012, Colombia
ORCID
Venue
Brain Sciences
Publisher
MDPI AG
Published
2022-06-30
Volume
12
Issue
7
Pages
871
ISSN
2076-3425 (ISSN-L)
DOI
10.3390/brainsci12070871
PMC
PMC9313109
OpenAlex
W4283757303
Cited by
17
References
3
Citations by year
2026: 2 · 2025: 1 · 2024: 9 · 2023: 4
FWCI
2.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Sciences (publishedVersion, cc-by)
  • Preprints.org (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repository University of Antioquia (University of Antioquia) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Keralty
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
PURA gene, de novo mutations, congenital hypotonia, neurodevelopmental delay, protein structure prediction, AlphaFold, protein-DNA docking

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