Mannosylated adamantane-containing desmuramyl peptide recognition by the NOD2 receptor: a molecular dynamics study

Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular receptor that recognizes the bacterial peptidoglycan fragment muramyl dipeptide (MDP). Our group has synthesized and biologically evaluated desmuramyl peptides containing adamantane and its mannose derivatives. The most active mannosylated derivative, ManAdDMP (Man-OCH₂-d-(1-Ad)Gly-l-Ala-d-isoGln), is further characterized in silico in this study. We built intact model structures of the rabbit NOD2 protein, whose crystal structure lacks seven loops, and explored the binding of ManAdDMP. Two main binding sites for ManAdDMP are located within the nucleotide-binding oligomerization domain (NOD) and C-terminal leucine-rich repeat (LRR) domains. Our analysis shows that the dipeptide isoGln moiety of ManAdDMP significantly contributes to the binding, whereas the mannose moiety interacts with modelled loop 7, which is a part of the NOD helical domain 2. The presented results point to the importance of loops 2 and 7 in ligand recognition that could be useful for further investigation of NOD2 activation/inhibition.