Elucidating the Trodusquemine Action Against Neurodegenerative Disorders by Molecular Modelling Techniques

Decanato - Facoltà di scienze informatiche

Data: 22 Giugno 2023 / 14:30 - 17:00

USI East Campus / Online

You are cordially invited to attend the PhD Dissertation Defence of Stefano Muscat on Thursday 22 June 2023 at 14:30 in room B1.12 and online.

The significant increase in life expectancy worldwide has drawn scientific attention to age-related pathologies, such as Alzheimer's disease (AD). The amyloid hypothesis assertsthat AD results from abnormal aggregation of specific amyloid proteins, leading to intracellular inclusions or extracellular aggregates in specific brain areas. Trodusquemine, an aminosterol isolated from the dogfish shark Squalus acanthias, has been found to modulate the kinetics of aggregation of the amyloid peptidesresponsible of AD. However, the mechanism by which aminosterols protectthe neuron interacting with thecell membranes and modulate their properties remains unclear.This PhD thesis employs computational molecular modelling to investigate trodusquemine molecularmechanism of action. Molecular dynamics (MD) simulations areusedto elucidate trodusquemine interaction with the cell membrane and its self-aggregation mechanism at the molecular level. Utilizing computational methodologies, the present study providesinsights intothe modulation of the cell membrane physicochemical properties by trodusquemine. Consequently, this modulation confersa reduced vulnerability of the cell membranes to the deleterious effects of misfolded protein aggregates.However, computational limitations often hinder the ability to investigate biomacromolecule conformational properties. The limitation mainly results from biological system’s rough energy landscapes, with many local minima separated by high-energy barriers. Therefore, MD simulations face the challenge of adequately sampling experimentally pertinent timescales ranging from milliseconds to seconds. Presently, classical MD simulations employing atomic resolution are confined to few microseconds. This work benefits from the development of a coarse-grain model to accelerate trodusquemine's dynamics and investigate supramolecular structures. Coarse-grain approach highlightsthe trodusquemine ability to modulate the coexistence of liquid-gel and liquid-disorder phases, influencing the lipid membrane thermodynamic stability. Furthermore, enhanced sampling techniques and dimensionality reduction methodologies areapplied to estimate fundamental thermodynamic properties of aminosterol molecules. The outcomes of this research represent an essential step in designing small molecules capable of protecting neuron cell membranes from the toxicity of amyloid oligomers.

Dissertation Committee:
- Prof. Andrea Danani, IDSIA USI-SUPSI, Switzerland (Research Advisor)
- Prof. Rolf Krause, Università della Svizzera italiana, Switzerland (Internal Member)
- Prof. Andrea Emilio Rizzoli, IDSIA USI-SUPSI, Switzerland (Internal Member)
- Prof. Marco Deriu, Politecnico di Torino, Italy (External Member)
- Prof. Giulia Rossi, Università di Genova, Italy (External Member)