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Computational and atomistic studies applied to the understanding of the structural and behavioral features of the immune checkpoint HLA-G molecule and gene

2023; Elsevier BV; Volume: 84; Issue: 8 Linguagem: Inglês

10.1016/j.humimm.2023.01.004

1879-1166

Cinthia C. Alves, Thaís Arns, Maria Luiza Guimarães de Oliveira, Philippe Moreau, Dinler A. Antunes, Erick C. Castelli, Celso Teixeira Mendes‐Junior, Silvana Giuliatti, Eduardo Antônio Donadi,

Reproductive Biology and Fertility

We took advantage of the increasingly evolving approaches for in silico studies concerning protein structures, protein molecular dynamics (MD), protein-protein and protein-DNA docking to evaluate: (i) the structure and MD characteristics of the HLA-G well-recognized isoforms, (ii) the impact of missense mutations at HLA-G receptor genes (LILRB1/2), and (iii) the differential binding of the hypoxia-inducible factor 1 (HIF1) to hypoxia-responsive elements (HRE) at the HLA-G gene. Besides reviewing these topics, they were revisited including the following novel results: (i) the HLA-G6 isoforms were unstable docked or not with β2-microglobulin or peptide, (ii) missense mutations at LILRB1/2 genes, exchanging amino acids at the intracellular domain, particularly those located within and around the ITIM motifs, may impact the HLA-G binding strength, and (iii) HREs motifs at the HLA-G promoter or exon 2 regions exhibiting a guanine at their third position present a higher affinity for HIF1 when compared to an adenine at the same position. These data shed some light into the functional aspects of HLA-G, particularly how polymorphisms may influence the role of the molecule. Computational and atomistic studies have provided alternative tools for experimental physical methodologies, which are time-consuming, expensive, demanding large quantities of purified proteins, and exhibit low output.