In SilicoScreening and Molecular Dynamics Simulation of Disease-Associated nsSNP in TYRP1 Gene and Its Structural Consequences in OCA3

Abstract

Oculocutaneous albinism type III (OCA3), caused by mutations of TYRP1 gene, is an autosomal recessive disorder characterized by reduced biosynthesis of melanin pigment in the hair, skin, and eyes. The TYRP1 gene encodes a protein called tyrosinase-related protein-1 (Tyrp1). Tyrp1 is involved in maintaining the stability of tyrosinase protein and modulating its catalytic activity in eumelanin synthesis. Tyrp1 is also involved in maintenance of melanosome structure and affects melanocyte proliferation and cell death. In this work we implemented computational analysis to filter the most probable mutation that might be associated with OCA3. We found R326H and R356Q as most deleterious and disease associated by using PolyPhen 2.0, SIFT, PANTHER, I-mutant 3.0, PhD-SNP, SNP&GO, Pmut, and Mutpred tools. To understand the atomic arrangement in 3D space, the native and mutant (R326H and R356Q) structures were modelled. Finally the structural analyses of native and mutant Tyrp1 proteins were investigated using molecular dynamics simulation (MDS) approach. MDS results showed more flexibility in native Tyrp1 structure. Due to mutation in Tyrp1 protein, it became more rigid and might disturb the structural conformation and catalytic function of the structure and might also play a significant role in inducing OCA3. The results obtained from this study would facilitate wet-lab researches to develop a potent drug therapies against OCA3.

Mutational Analysis of Oculocutaneous Albinism: A Compact Review

“…The structural analyses of native and mutant Tyrp1 proteins were scrutinized by molecular modelling and molecular dynamics simulation (MDS) approach. From this analysis we confirmed that, TYRP1 protein alter the structural conformation and loss the flexibility behaviour upon mutation [75]. The structural alteration of TYRP1 protein upon mutation was clearly discussed and shown in our previous studies (Figure 4) [75].…”

In Silico identification of SNP diversity in cultivated and wild tomato species: insight from molecular simulations

“…Molecular simulation analysis revealed the SNPs influence over the proteins playing a role in the defense response (PR1) and metabolic activities; both are noteworthy phenotypic difference known to exist in both the species. A similar approach was applied in earlier studies434445 to study the influence of non-synonymous SNPs. Present study must enhance the knowledge of the scientific community and provide support for the future breeding program.…”

In-silico analysis of non-synonymous-SNPs of STEAP2: To provoke the progression of prostate cancer

“…The organized platform for the analysis and estimations of pathological consequence of genetic mutations and in determining their basic molecular mechanism [8][9][10][11][12][13]. In this study, we have tried to find out most deleterious and disease associated nsSNPs in coding region of STEAP2 out of dataset obtained from ENSEMBL by using computational tools and then checked their effects on structure of protein [13,14].…”

“…PolyPhen2 calculates the probability for a given mutation to be benign, possibly damaging or probably damaging. If score is nearer to 1, nsSNPs will probably be damaging [11,19].…”