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

IF 3 3区化学 Q3 CHEMISTRY, PHYSICAL

Computational and Theoretical Chemistry Pub Date : 2025-02-01 DOI:10.1016/j.comptc.2024.115039

Mengguo Chen , Fanru Yuan , Huijian Zhao , Zhili Yin , Shaohui Liu , Hongmin Liu , Longhua Yang

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Abstract

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.

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来源期刊

Computational and Theoretical Chemistry CHEMISTRY, PHYSICAL-

CiteScore

4.20

自引率

10.70%

发文量

331

审稿时长

31 days

期刊介绍： Computational and Theoretical Chemistry publishes high quality, original reports of significance in computational and theoretical chemistry including those that deal with problems of structure, properties, energetics, weak interactions, reaction mechanisms, catalysis, and reaction rates involving atoms, molecules, clusters, surfaces, and bulk matter.