Alves Cinthia C, Lewis Jaila, Antunes Dinler A, Donadi Eduardo A
Department of Medicine, Division of Clinical Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil.
Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5001, USA.
Int J Mol Sci. 2024 Dec 24;26(1):34. doi: 10.3390/ijms26010034.
Citrullination, a post-translational modification (PTM), plays a critical role in rheumatoid arthritis (RA) by triggering immune responses to citrullinated self-antigens. Some HLA-DRB1 genes encode molecules with the shared epitope (QKRAA/QRRAA) sequence in the peptide-binding groove which preferentially presents citrulline-modified peptides, like vimentin, that intensifies the immune response in RA. In this study, we used computational approaches to evaluate intermolecular interactions between vimentin peptide-ligands (with/without PTM) and HLA-DRB1 alleles associated with a significantly increased risk for RA development. Crystal structures for HLA-DRB1*04:01, *04:04, and *04:05 bound to citrullinated peptides (PDB ID: 4MCY, 4MD5, 6BIR) were retrieved from the Protein Data Bank and non-citrullinated 3D structures were generated by mutating citrulline to arginine. The pHLA complexes were submitted to four rounds (50 ns each) of molecular dynamic simulations (MD) with Gromacs v.2022. Our results show that citrulline strengthens the interaction between vimentin and the HLA-DRB1 molecules, therefore impacting both the peptide affinity to the HLAs and pHLA stability; it also induces more intermolecular hydrogen bond formation during MD in the pHLA. Citrulline prevents repulsion between amino acid 71β and the P4-residue of native vimentin. Thus, vimentin citrullination seems to affect pHLA binding and dynamics, which may influence RA-related immune responses.
瓜氨酸化是一种翻译后修饰（PTM），通过触发对瓜氨酸化自身抗原的免疫反应，在类风湿性关节炎（RA）中发挥关键作用。一些HLA - DRB1基因在肽结合槽中编码具有共享表位（QKRAA/QRRAA）序列的分子，这些分子优先呈递瓜氨酸修饰的肽，如波形蛋白，从而增强RA中的免疫反应。在本研究中，我们使用计算方法评估波形蛋白肽配体（有/无PTM）与与RA发生风险显著增加相关的HLA - DRB1等位基因之间的分子间相互作用。从蛋白质数据库中检索了与瓜氨酸化肽结合的HLA - DRB1*04:01、04:04和04:05的晶体结构（PDB ID：4MCY、4MD5、6BIR），并通过将瓜氨酸突变为精氨酸生成非瓜氨酸化的三维结构。使用Gromacs v.2022对pHLA复合物进行四轮（每轮50 ns）分子动力学模拟（MD）。我们的结果表明，瓜氨酸增强了波形蛋白与HLA - DRB1分子之间的相互作用，因此影响了肽与HLA的亲和力以及pHLA的稳定性；它还在pHLA的MD过程中诱导更多分子间氢键形成。瓜氨酸可防止71β位氨基酸与天然波形蛋白的P4残基之间的排斥。因此，波形蛋白瓜氨酸化似乎会影响pHLA的结合和动力学，这可能会影响与RA相关的免疫反应。
