Intrinsic deformability of human acetylcholinesterase in presence of diverse compounds: a biophysical-computational study based on classical dynamics, elastic network models, statistical potentials, energy frustration, and cavity volumetry

Lenin González-Paz; José Luis Paz; Marcos A. Loroño-González; Julio Santiago Contreras; Carla Lossada; Alejandro Vivas; Yovani Marrero-Ponce; Felix Martinez-Rios; Patricia Rodríguez-Lugo; Yanpiero Balladores; Joan Vera-Villalobos; Ysaias J. Alvarado

doi:10.20944/preprints202407.1422.v1

Preprint Article Version 1 This version is not peer-reviewed

Version 1 : Received: 16 July 2024 / Approved: 17 July 2024 / Online: 17 July 2024 (11:27:37 CEST)

The enzyme acetylcholinesterase (AChE) plays a crucial role in the termination of nerve impulses by hydrolyzing the neurotransmitter acetylcholine (ACh). The inhibition of AChE has emerged as a promising therapeutic approach for the management of neurological disorders such as Lewy body dementia and Alzheimer's disease. The potential of various compounds as AChE inhibitors has been investigated. In this study, we evaluated the impact of natural compounds of interest on the intrinsic deformability of human AChE using computational biophysical analysis. Our approach incorporates classical dynamics, elastic networks, statistical potentials, energy frustration, and volumetric cavity analyses. The results revealed that cyanidin induced significant changes in the flexibility and rigidity of AChE, especially in the distribution and volume of internal cavities, compared to model inhibitors such as TZ2PA6, and through a distinct biophysical-molecular mechanism from the other inhibitors considered. These findings suggest that cyanidin could offer potential mechanistic pathways for future research and applications in the development of new treatments for neurodegenerative diseases.

Alzheimer's disease; structural flexibility; AChE inhibitors

Computer Science and Mathematics, Mathematical and Computational Biology

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Intrinsic deformability of human acetylcholinesterase in presence of diverse compounds: a biophysical-computational study based on classical dynamics, elastic network models, statistical potentials, energy frustration, and cavity volumetry

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