Computational simulation study of the mutation effects on the interaction mechanisms of LSD1 with histone H3 and non-histone Snail1 substrates

Three newly identified pathological mutations (Glu379Lys, Asp556Gly, Tyr761His) in histone lysine-specific demethylase 1 (LSD1) are associated with a novel genetic disorder. To understand how they affect the properties of this chromatin-associated enzyme at the atomic level, this study investigated the interaction mechanisms of wild-type and mutated LSD1 with histone H3 and non-histone Snail1 substrates using a combination of virtual mutations, molecular dynamics simulations, and free energy calculations. Results show Glu379Lys causes the most significant decrease in binding affinity and catalytic ability due to charge reversal, with effects varying at different terminals for different substrates. Asp556Gly’s impact is minimized by compensation from adjacent Asp555 and Asp553. Tyr761His affects binding and catalytic abilities through altered relative positions of Tyr761/Tyr761His, Met4/Phe4, and FAD. This research establishes a theoretical foundation for investigating the pathological mechanism in patients with these separate mutations, and holds value for further designing specific LSD1 inhibitors for their treatment.