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

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

Authors :
Shaik, Noor A.
Bokhari, Hifaa A.
Masoodi, Tariq Ahmed
Shetty, Preetha J.
Ajabnoor, Ghada M. A.
Elango, Ramu
Banaganapalli, Babajan
Source :
Journal of Biomolecular Structure and Dynamics; September 2020, Vol. 38 Issue: 14 p4067-4080, 14p
Publication Year :
2020

Abstract

AbstractCarbonic 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

Details

Language :
English
ISSN :
07391102 and 15380254
Volume :
38
Issue :
14
Database :
Supplemental Index
Journal :
Journal of Biomolecular Structure and Dynamics
Publication Type :
Periodical
Accession number :
ejs54033131
Full Text :
https://doi.org/10.1080/07391102.2019.1671899