1st International and 10th National Iranian Conference on Bioinformatics
Home Accepted Papers
Investigating the effects of carboxyl terminal elimination from 604 retinal isoform of IMPDH1: an experimental and molecular dynamics simulation approach
Paper ID : 1078-ICB10
Authors:
Parisa Elyasi Ebli *1, Razieh Yazdanparast2, Sajjad Gharaghani3
1No. 8- 164 alley- 162 street- 2nd square- Farjam Street- Tehranpars.
2گروه بیوشیمی- مرکز تحقیقات بیوشیمی و بیوفیزیک-دانشگاه تهران-تهران-ایران
3گروه بیوانفورماتیک-مرکز تحقیقات بیوشیمی و بیوفیزیک-دانشگاه تهران-تهران ایران
Abstract:
Mutations in inosine monophosphate dehydrogenase 1 (IMPDH1), are known to be a root cause of Retinitis Pigmentosa (RP), a common hereditary blindness [1]. Regulation of the activity of IMPDH1 is dependent on the occupation of nucleotide binding sites with GDP/GTP, performing an inhibitory effect [2]. The retinal isoforms of IMPDH1, identified with distinct catalytic activity, contain additional terminal peptides which their possible roles in regulation of enzymatic activity relies undiscovered [1]. The current study investigated the probable interactions of N-ter peptide extension of 604-isoform in absence of the C-ter peptide. MD simulations on dimer structures of wild-type and engineered proteins were performed using GROMACS 2019.1 simulation Package and CHARMM36 force field. The energy of the system was minimized and the system was equilibrated using Velocity-rescaling and Parrinello-Rahman algorithms for NVT and NPT equilibrations, respectively. The final production step of the system continued up to 20 ns. Further, RMSD and RMSF analyses were performed. The proteolytic digestion indicated a rapid digestion of the recombinant protein in contrast to the wild type 604-isoform, recommending a higher accessibility of α-Chymotrypsin to digestion sites due to the removal of C-ter peptide. Our computational data, also, revealed the formation of a novel helix of N-ter peptide in GTP2 binding site. This helix formation could affect the regulation of enzyme's catalytic activity, either by masking the nucleotide binding site or acting as an GTP-independent internal inhibitory element.

[1] Andashti, B. et al. (2020). The functional impact of the C/N-terminal extensions of the mouse retinal IMPDH1 isoforms: a kinetic evaluation. Molecular and cellular biochemistry, 465(1-2), 155–164.
[2] Buey, R. M. et al. (2015). Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases. Nature communications, 6, 8923
Keywords:
Retinitis Pigmentosa; IMPDH1; Moleular Dynamics Simulation; retinal isoforms.
Status : Paper Accepted (Poster Presentation)