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

Hui Zhang; Jilong Zhang; Hong-Xing Zhang

doi:10.1016/j.jmgm.2024.108778

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

J Mol Graph Model. 2024 Apr 17:130:108778. doi: 10.1016/j.jmgm.2024.108778. Online ahead of print.

Authors

Hui Zhang¹, Jilong Zhang², Hong-Xing Zhang³

Affiliations

¹ Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun, 130023, Jilin, People's Republic of China.
² Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun, 130023, Jilin, People's Republic of China. Electronic address: jilongzhang@jlu.edu.cn.
³ Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun, 130023, Jilin, People's Republic of China. Electronic address: zhanghx@jlu.edu.cn.

PMID: 38652998
DOI: 10.1016/j.jmgm.2024.108778

Abstract

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.

Keywords: HDACs; MD simulations; Mono-ADP ribosylation; Quercetin; SIRT6.