Structural insights into Leishmania donovani mevalonate kinase and its interaction with toll-like receptors during early infection

Leishmania donovani mevalonate kinase (LdMVK) is crucial for isoprenoid and sterol biosynthesis, making it a potential target for both drugs and vaccines. Structural and immunological studies revealed its stability (pI 9.22, aliphatic index 89.54, instability index 31.42) and suitability for in vivo use. Negative GRAVY score and positive charge favor TLR-4 interaction. Conserved GHMP motifs validate enzymatic activity, while balanced secondary structures (42.55% helices, 42.25% coils) indicate structural flexibility and stability. The 3D model predicted the structure to retain its integrity, and the refined structure from a Ramachandran plot confirmed 99.3% of residues in favored regions with further support from an ERRAT quality score of 95.23.Molecular docking experiments revealed specific and stable interactions of LdMVK with TLR-2 and TLR-4, including important electrostatic and hydrogen bonding residues. Molecular dynamics simulations for 100 ns validated the structural stability of LdMVK and its receptor complexes, with RMSD, Rg, and RMSF analyses confirming conformational flexibility. The TLR-2–LdMVK complex had a larger number of stable hydrogen bonds (8–16) than the TLR-4 complex (5–12), suggesting greater interaction. Immune simulations by C-ImmSim showed intense activation of macrophages, B cells, and dendritic cells and the induction of antigen-specific memory responses. Overall, these data affirm LdMVK's potential as an immunogen and a new vaccine candidate for Leishmania donovani.