Title: Polymorphism in the ligand binding domain of rage alters its binding affinity towards Aβ42 peptides: an in-silico study

Authors: Sreeram Krishnan; P. Rani

Addresses: Department of Biotechnology, PSG College of Technology, Peelamedu, Coimbatore 641004, Tamil Nadu, India ' Department of Biotechnology, PSG College of Technology, Peelamedu, Coimbatore 641004, Tamil Nadu, India

Abstract: The study was aimed to understand the influence of RAGE polymorphism (G82S, R48Q, R77C) on the binding affinity to Aβ42 peptides through an in-silico approach. The structure of RAGE ectodomain (3CJJ) was docked with three forms of Aβ42 [monomeric: apolar environment (1IYT), polar environment (1Z0Q) and fibrillar (2BEG)] using CLUSPRO in antibody mode. Highest binding score was observed with 2BEG indicating enhanced affinity of RAGE towards fibrillar Aβ42. Amino acid modifications were done in RAGE sequence to create variants and their structures were generated using SWISS MODEL followed by molecular dynamics simulation in GROMACS. The lowest energy structures (10 nos.) were then docked with Aβ42 peptides. Compared to wtRAGE, G82S variant showed higher affinity whereas R48Q variant showed lesser affinity to all three forms of Aβ42. R77C variant showed significant decrease in affinity compared to wtRAGE when docked with 1IYT, and increased affinity with the other forms. The results of the study indicate that RAGE polymorphisms could modify the affinity of RAGE towards Aβ42.

Keywords: RAGE polymorphism; advanced glycation end product; AGE; receptor for AGE; Alzheimer's disease; sRAGE; Aβ42 peptides; molecular dynamics; protein peptide docking; bioinformatics; ligand binding; binding affinity; amino acid modifications; molecular dynamics; simulation.

DOI: 10.1504/IJBRA.2016.078226

International Journal of Bioinformatics Research and Applications, 2016 Vol.12 No.3, pp.181 - 193

Accepted: 12 Dec 2015
Published online: 01 Aug 2016 *

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