title: Casting the critical regions in nucleotide binding oligomerization domain 2 protein: a signature mediated structural dynamics approach.
abstract: Nucleotide binding oligomerization domain 2 (NOD2), a protein involved in the first line defence mechanism has a pivotal role in innate immunity. Impaired function of this protein is implicated in disorders such as Blau syndrome and Crohn's disease. Since an altered function is linked to protein's structure, we framed a systematic strategy to interpret the structure-function relationship of the protein. Initiated with mutation-based pattern prediction and identified a distant ortholog (DO) of NOD2 from which the intra-residue interaction network was elucidated. The network was used to identify hotspots that serve as critical points to maintain the stable architecture of the protein. Structural comparison of NOD2 domains with a DO revealed the minimal number of intra-protein interactions required by the protein to maintain the structural fold. In addition, the conventional molecular dynamics simulation emphasized the conformational transitions at hot spot residues between native NOD2 domains and its respective mutants (G116R, R42W and R54A) structures. The analysis of intra-protein interactions globally and the displacement of residues locally around the mutational site revealed loss of several critical bonds and residues vital for the protein's function. Conclusively we report, about 10 residues in leucine-rich repeat, 13 residues in NOD and 6 residues in CARD domain are required by the NOD2 to maintain its function. This protocol will help the researchers to achieve for more prospective studies to attest druggable site utility in discovering novel drug candidates.
authors: a Department of Biotechnology , School of Bioscience and Technology, VIT University , Vellore 632301 , India.
authors: P
authors: P
authors: Raghuraman
authors: a Department of Biotechnology , School of Bioscience and Technology, VIT University , Vellore 632301 , India.
authors: R
authors: R
authors: Jesu Jaya Sudan
authors: a Department of Biotechnology , School of Bioscience and Technology, VIT University , Vellore 632301 , India.
authors: J
authors: J
authors: Lesitha Jeeva Kumari
authors: a Department of Biotechnology , School of Bioscience and Technology, VIT University , Vellore 632301 , India.
authors: C
authors: C
authors: Sudandiradoss
mesh_terms: D001665:Binding Sites; D000071476:Caspase Activation and Recruitment Domain; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D053473:Nod2 Signaling Adaptor Protein / Q000737:chemistry*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D055503:Protein Multimerization; D020449:Repetitive Sequences, Amino Acid
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein
keywords: NOD2; distant ortholog; molecular dynamics; mutagenesis; sequence motif; signature