Effect of quercetin on the protein-substrate interactions in SIRT6: Insight from MD simulations

SIRT6 is of interest for its promising effect in the treatment of aging-related diseases. Studies have shown quercetin (QUE) and its derivatives have varying degrees of effect on the catalytic effect of SIRT6. In the research, the effect of QUE on the protein-substrate interaction in the SIRT6-mediated mono-ADP ribosylation system was investigated by conventional molecular dynamics (MD) simulations combined with MM/PBSA binding free energy calculations. The results show that QUE can bind stably to SIRT6 with the binding energy of -22.8 kcal/mol and further affect the atomic interaction between SIRT6 and NAD⁺ (or H3K9), resulting in an increased affinity between SIRT6-NAD⁺ and decreased SIRT6-H3K9 binding capacity. At the same time, the binding of QUE can also alter some structural characteristics of the protein, with large shifts occurring in the residue regions involving the N-terminal (residues 1-27), Rossmann fold regions (residues 55-92), and ZBD (residues 164-179). Thus, QUE shows great potential as a scaffold for the design of novel potent SIRT6 modulators.