Structural comparison between human and Leishmania infantum Sirtuin 2 NAD-dependent histone deacetylases

• The LiSIR2rp1 regions absent in its crystal are IDRs. • A complete model for LiSIR2rp1 was generated, including its IDRs. • The LiSIR2rp1 catalytic core is conserved and structurally very close to hSIRT2. • The LiSIR2rp1 and hSIRT2 catalytic cores exhibit stability in molecular dynamics. • The LiSIR2rp1 central IDR and hSIRT2 loop exhibit flexibility despite length difference. Leishmaniasis is a protozoan disease prevalent in subtropical regions. Its treatment is expensive, especially the liposomal formulation, and parasite resistance must sometimes be overcome. The Sirtuins are a family of NAD-dependent histone deacetylases that have been identified as promising targets for anti-parasitic drugs due to their essential roles in organisms such as Leishmania. There are three known sirtuins in Leishmania infantum : SIR2-related protein 1 (LiSIR2rp1) present in the cytoplasm and nuclei, and LiSIR2rp2-3 present in mitochondria. While a truncated version of the LiSIR2rp1 has already been crystallized, the complete molecular structure remains unresolved. Our study presents a structural computational characterization of the full-length LiSIR2rp1, the non-mitochondrial sirtuin homologous to human sirtuin SIRT2. We generated and validated molecular models for the full-length LiSIR2rp1 using computational tools. The protein presented a highly conserved catalytic core, and the molecular dynamics simulations (MDS) revealed structural stability of this core, similar to that of human sirtuins. However, the LiSIR2rp1 highly flexible central intrinsically disordered region (IDR) simulated an overall MDS instability. These results suggest that the IDR conformational freedom plays a critical role in the functioning of LiSIR2rp1, with a similar loop in hSIRT2. Our findings contribute to a better understanding of LiSIR2rp1′s structural patterns and compare it to its human homolog, thus offering insights into its behaviour. Knowledge about this L. infantum enzyme, a potential target for drug development, could enhance the prospects for future therapeutic strategies against leishmaniasis.