Multiscale Modelling of TDP-43

Speaker: Zahra Raza
Date: Thursday July 2, 1pm – 2pm AEST
Zoom: Click here to join the seminar

Abstract:

Neurodegenerative diseases like ALS and dementia affect millions worldwide, leading to a tragic loss of life and quality of life. A key player in these diseases is a protein called TAR DNA binding Protein or TDP-43. Normally, TDP-43 forms protective structures called biomolecular condensates through a process known as liquid-liquid phase separation. However, under certain conditions, TDP-43 can misbehave and can form toxic aggregates that damage neurons, leading to neurodegeneration. Adenosine triphosphate (ATP), most well known as the energy molecule of cells has emerged as an important modulator of biomolecular condensates and protein aggregation. Numerous experimental and computational studies have demonstrated ATP’s role in solubilizing many kinds of proteins, including TDP-43, however the molecular mechanisms remain poorly understood.

Molecular dynamics simulations can provide the means to investigating ATP-protein interactions at the molecular level. However, a major drawback exists whereby current ATP model vastly overestimate the self-aggregation ability of ATP. Whilst some models exist to improve ATP properties in all-atom resolution, none such exist at a coarse-grained resolution. To address this we are developing a coarse-grained ATP model with improved self-association behaviour which will provide a foundation for future simulations aimed at understanding how ATP modulates TDP-43 phase separation.

Bio:
Zahra is a third-year PhD candidate at the University of Wollongong, supervised by Professor Haibo Yu and Professor Lezanne Ooi, and supported by CSIRO’s Next Generation Graduates Program. Her research focuses on the multiscale modelling of TDP-43, which is an RNA-binding protein that is s implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Using molecular dynamics simulations and multiscale modelling techniques, Zahra investigates the structural dynamics, intermolecular interactions, and aggregation-prone behaviour of TDP-43. Through this work, she seeks to improve the understanding of the molecular mechanisms underlying TDP-43 misfolding and aggregation in neurodegenerative disease, with the long-term goal of contributing to the development of future therapeutic strategies.