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Molecular modelling and dynamics of CA2 missense mutations causative to carbonic anhydrase 2 deficiency syndrome.

Authors
  • Shaik, Noor A1, 2
  • Bokhari, Hifaa A1
  • Masoodi, Tariq Ahmed3
  • Shetty, Preetha J4
  • Ajabnoor, Ghada M A5
  • Elango, Ramu1, 2
  • Banaganapalli, Babajan1, 2
  • 1 Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. , (Saudi Arabia)
  • 2 Princess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia. , (Saudi Arabia)
  • 3 Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. , (Saudi Arabia)
  • 4 Department of Biomedical Sciences, College of Medicine, Gulf Medical University, Ajman, UAE.
  • 5 Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. , (Saudi Arabia)
Type
Published Article
Journal
Journal of biomolecular structure & dynamics
Publication Date
Sep 01, 2020
Volume
38
Issue
14
Pages
4067–4080
Identifiers
DOI: 10.1080/07391102.2019.1671899
PMID: 31542996
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Carbonic anhydrase 2 (CA2) enzyme deficiency caused by CA2 gene mutations is an inherited disorder characterized by symptoms like osteopetrosis, renal tubular acidosis, and cerebral calcification. This study has collected the CA2 deficiency causal missense mutations and assessed their pathogenicity using diverse computational programs. The 3D protein models for all missense mutations were built, and analyzed for structural divergence, protein stability, and molecular dynamics properties. We found M-CAP as the most sensitive prediction method to measure the deleterious potential of CA2 missense mutations. Free energy dynamics of tertiary structure models of CA2 mutants with DUET, mCSM, and SDM based consensus methods predicted only 50% of the variants as destabilizing. Superimposition of native and mutant CA2 models revealed the minor structural fluctuations at the amino acid residue level but not at the whole protein structure level. Near native molecular dynamic simulation analysis indicated that CA2 causative missense variants result in residue level fluctuation pattern in the protein structure. This study expands the understanding of genotype-protein phenotype correlations underlying CA2 variant pathogenicity and presents a potential avenue for modifying the CA2 deficiency by targeting biophysical structural features of CA2 protein. Communicated by Ramaswamy H. Sarma.

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