Programme

I.4 -- Invited, VCTP-48

Date: Monday, 31 July 2023

Time: 15:45 - 16:25

Investigating active structures of NLRP3-NACHT protein at atomic scale using computational tools

Hien T. T. Lai, Tran-Nam Nguyen, Ha M. Do, Toan T. Nguyen

Key Laboratory for Multiscale Simulation of Complex Systems, and Department of Theoretical Physics, University of Science, Vietnam National University

Since the discovery of the NLRP3 inflammasome by F. Martin and J. Tschopp in 2001 to the present, a large amount of experimental results on cell lines and animal models has shown that NLRP3 has been implicated in many forms of human chronic disease. More specifically, the relationship of NLRP3 activation to the formation and progression of inflammatory diseases such as hepatitis, enteritis, rheumatoid arthritis and gout... At present, NLRP3 is a drug target, however, the understanding of the mechanism of NLRP3 activation, as well as the activators and inhibitors of this process is still unclear. With our previous theoretical work and experimental evidence showing the role of ATP in interacting with and activating the NATCH region of NLRP3, the model is correct. In this study, we continue to use bioinformatics tools, MD with some advantages to evaluate the competitive impact of the interaction between ATP and NACHT of colchicine (named shortly COL) - a compound that has been shown to be effective in diseases associated with NLRP3 such as gout, cardiovascular disease. We docked colchicine to the ATP binding pocket as well as other potential pockets in mouse NACHT model. The best COL configures at pockets with lowest binding scores were chosen underwent molecular dynamics (MD) simulation. Our results show that (i) all systems NACHT-COL are stable after first 20ns simulation time; (ii) COL bind stably to the ATP binding pocket and two other potential pockets of mouse NACHT domain according to high distribution of hydrophobic and van der Waal interactions. While hydrogen bond (Hbond) and electrostatic interactions are important types of contact for keeping ATP at its NACHT pocket; (iii) the compound COL has higher binding energies in other potential pockets than in the ATP pocket. This study provides the activity mechanics of NLRP3 protein and insights into virtual screen phytocompounds with high binding affinity for gout treatments.

Presenter: Nguyen The Toan