Beta-2 microglobulin (β2m) is an amyloidogenic protein belonging to the immunoglobulin superfamily, responsible for the dialysis-related amyloidosis (DRA).

Rajasekaran R

Department of Biotechnology

School of Bio Sciences and Technology

Vellore Campus

Chandrasekaran P

Vellore Institute of Technology (VIT) is a private university located in&nbsp;Tamil Nadu, India. Founded in 1984, as Vellore Engineering College, the institution offers 20 undergraduate, 34 postgraduate, four integrated and four research programs. It has campuses in Vellore, Amravati, Bhopal and Chennai.

VIT is one of the top ranked private universities in India according to NIRF, THE and QS Rankings.&nbsp;Govt. of India has recognized&nbsp;VIT, Vellore as an&nbsp;Institution of Eminence. This has allowed VIT to take independent quality initiatives and move up in world ranking.

&nbsp;

&nbsp;

VIT University

Molecular BioSystems

Schindler disease is a lysosomal storage disorder caused due to deficiency or defective activity of alpha-N-acetylgalactosaminidase (α-NAGA). Mutations in gene encoding α-NAGA cause wide range of diseases, characterized with mild to severe clinical features. Molecular effects of these mutations are yet to be explored in detail. Therefore, this study was focused on four missense mutations of α-NAGA namely, S160C, E325K, R329Q and R329W. Native and mutant structures of α-NAGA were analysed to determine geometrical deviations such as the contours of root mean square deviation, root mean square fluctuation, percentage of residues in allowed regions of Ramachandran plot and solvent accessible surface area, using conformational sampling technique. Additionally, global energy-minimized structures of native and mutants were further analysed to compute their intra-molecular interactions, hydrogen bond dilution and distribution of secondary structure. In addition, docking studies were also performed to determine variations in binding energies between native and mutants. The deleterious effects of mutants were evident due to variations in their active site residues pertaining to spatial conformation and flexibility, comparatively. Hence, variations exhibited by mutants, namely S160C, E325K, R329Q and R329W to that of native, consequently, lead to the detrimental effects causing Schindler disease. This study computationally explains the underlying reasons for the pathogenesis of the disease, thereby aiding future researchers in drug development and disease management. © 2016, International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag Berlin Heidelberg.

Interdisciplinary Sciences: Computational Life Sciences

Exploration of Structural and Functional Variations Owing to Point Mutations in α-NAGA

Journal of Cellular Biochemistry

Deciphering the Molecular Effects of Mutations on ATRX Cause ATRX Syndrome: A Molecular Dynamics Study

Natowicz syndrome (mucopolysaccharidoses type 9) is a lysosomal storage disorder caused by deficient or defective human hyaluronidase 1. The disorder is not well studied at the molecular level. Therefore, a new in silico approach was proposed to study the molecular basis on which one clinically observed mutation, Glu268Lys, results in a defective enzyme. The native and mutant structures were subjected to comparative analyses using a conformational sampling approach for geometrical variables viz, RMSF, RMSD, and Ramachandran plot. In addition, the strength of a Cys207–Cys221 disulfide bond and electrostatic interaction between Arg265 and Asp206 were studied, as they are known to be involved in the catalytic activity of the enzyme. Native and mutant E268K showed statistically significant variations with p < 0.05 in RMSD, Ramachandran plot, strengths of disulfide bond, and electrostatic interactions. Further, single model analysis showed variations between native and mutant structures in terms of intra-protein interactions, hydrogen bond dilution, secondary structure, and dihedral angles. Docking analysis predicted the mutant to have a less favorable substrate binding energy compared to the native protein. Additionally, steered MD analysis indicated that the substrate should have more affinity to the native than mutant enzymes. The observed changes theoretically explain the less favorable binding energy of substrate towards mutant E268K, thereby providing a structural basis for its reduced catalytic activity. Hence, our study provides a basis for understanding the disruption in the molecular mechanism of human hyaluronidase 1 by mutation E268K, which may prove useful for the development of synthetic chaperones as a treatment option for Natowicz syndrome. © 2016, European Biophysical Societies' Association.

European Biophysics Journal

In silico approach to explore the disruption in the molecular mechanism of human hyaluronidase 1 by mutant E268K that directs Natowicz syndrome

X-linked lymphoproliferative (XLP) syndrome is an extremely rare inherited immunodeficiency disease characterized by severe immune dysregulation caused by mutations in signaling lymphocyte activation molecule (SLAM) associated protein (SAP) gene. The XLP syndrome was manifested due to dysfunction of SAP as a result of amino acid substitution. Hence, to understand the molecular aspects of the XLP syndrome, we structurally characterized two observed mutations, R32Q and T53I on SAP through the systematic molecular dynamics (MD) approach. Our MD analysis showed that mutant structures elucidated an atomic level variation influenced by mutations that substantially altered the residual flexibility and more importantly the hot spot residues as well in unbound and bound systems. In addition, change in residual flexibility of mutant structures showed an unusual conformational behavior associated with their molecular recognition function compared to the wild-type SAP in both systems. Besides, both mutant structures established different secondary structural profiles during the course of the simulation period in both systems. Moreover, the docking analysis revealed that mutant R32Q and T53I structures displayed remarkably reduced levels of binding affinity to the unphosphorylated SLAM peptide with respect to their docking scores. Collectively, our findings provide knowledge to understand the structural and functional relationship of disease-causing mutations, R32Q and T53I on SAP as well as gain further insights into the molecular pathogenesis of the XLP syndrome. This journal is © the Partner Organisations 2014.

Structural characterization of disease-causing mutations on SAP and the functional impact on the SLAM peptide: a molecular dynamics approach

PLOS ONE

Wild Type Beta-2 Microglobulin and DE Loop Mutants Display a Common Fibrillar Architecture

PLoS Computational Biology

A Simulated Intermediate State for Folding and Aggregation Provides Insights into ΔN6 β2-Microglobulin Amyloidogenic Behavior

Journal of Biological Chemistry

Class I Major Histocompatibility Complex, the Trojan Horse for Secretion of Amyloidogenic β2-Microglobulin

Mol. BioSyst.

Insights into the role of the beta-2 microglobulin D-strand in amyloid propensity revealed by mass spectrometry

A systematic molecular dynamics approach to the structural characterization of amyloid aggregation propensity of β2-microglobulin mutant D76N

Journal	Data powered by TypesetMolecular BioSystems
Publisher	Data powered by TypesetRoyal Society of Chemistry (RSC)
ISSN	1742-206X
Open Access	No