{'fraction_non_alphanumeric': 0.024704065877509007, 'fraction_numerical': 0.027277406073082863, 'mean_word_length': 5.657534246575342, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Structural localization of pathogenic mutations in the central nucleotide-binding domain (NBD) of nucleotide-binding oligomerization domain-2 (NOD2) protein and their inference in inflammatory disorders

Abstract The human NBD domain which is centrally located in the NOD2 protein displays an essential role in oligomerization and initiates the immune response via CARD-RIPK2 interaction. The mutations associated with the NBD domain have been largely implicated in inflammatory disorders such as Blau syndrome and sarcoidosis. This study aims to determine the structural and phenotypic effect of a lethal mutation that occurs in the NBD domain which has an axiomatic impact on protein dysfunction. Initially, the most deleterious missense mutations were screened through various in silico analysis. Out of 33 variants, I-Mutant 3.0, SIFT, PolyPhen 2, Align GVGD, PHD SNP and SNP&GO have statistically identified 5 variants (R42W, D90E, E91K, G189D & W198L) as less stable, deleterious and damaging. Our predicted models have paved the way to understand the various structural properties such as physiochemical, secondary structural arrangements and stabilizing residues in folding associated with the native and mutant NBD domain especially of the functionally important regions. From the aforementioned results, R42W and G189D were found to be the more predominant among the mutants. Precisely, through molecular simulation, we have strongly justified the significant conformational disruption of R42W and G189D through the stabilization factors, folding and essential dynamics. Conclusively, these regions (α341-44, α13185-191 and β6133-143β7) seem to adopt such structures that are not conducive to wild-type-like functionality. Our prediction and validation of lethal mutations based on structural stability may be useful for conducting experimental studies in detail to uncover the protein deregulation leading to inflammatory disorders.