Exploring the association of rs10490924 polymorphism with age-related macular degeneration: An in silico approach

Abstract

The polymorphism rs10490924 (A69S) in the age-related maculopathy susceptibility 2 (ARMS2) gene is highly associated with age-related macular degeneration, which is the leading cause of blindness among the elderly population. ARMS2 gene encodes a putative small (11 kDa) protein, which the function and localization of the ARMS2 protein remain under debate. For a better understanding of functional impacts of A69S mutation, we performed a detailed analysis of an ARMS2 sequence with a broad set of bioinformatics tools. In silico analysis was followed to predict the tertiary structure, putative binding site regions, and binding site residues. Also, the effects of this mutation on protein stability, aggregation propensity, and homodimerization were analyzed. Next, a molecular dynamic simulation was carried out to understand the dynamic behavior of wild-type, A69S, and phosphorylated A69S structures. The results showed alterations in the putative post-translational modification sites on the ARMS2 protein, due to the mutation. Furthermore, the stability of protein and putative homodimer conformations were affected by the mutation. Molecular dynamic simulation results revealed that A69S mutation enhances the rigidity of the ARMS2 structure and residue serine at position 69 is buried and may not be phosphorylated; however, phosphorylated serine enhances the flexibility of the ARMS2 structure. In conclusion, our study provides new insights into the deleterious effects of A69S mutation on the ARMS2 structure. (C) 2018 Elsevier Inc. All rights reserved.