Computational Structural Investigation of Molecular Interactions in Cancer Biology and Neurological Disorders

This proposal encompasses two distinct projects being undertaken by my group. The first of focuses on understanding the structural and biophysical basis of signal transduction in the Wnt signalling pathway. The second of these examines substrate recognition and processing by the Alzheimer's disease-associated protein, gamma-secretase, DNA recognition by natural variants of the neurodevelopment-associated transcription factor ZBTB18

Principal investigator

Mark Agostino
Magnifying glass

Area of science

Biomolecular modelling, Health, molecular dynamics

Systems used

Magnus and Zeus

Applications used

Partner Institution: Curtin University| Project Code: pawsey0196

The Challenge

Understanding the structural and biophysical basis of signal transduction in Wnt signalling will allow for the development of anti-cancer therapeutics targeting this pathway. Understanding how gamma-secretase processes its various substrates will allow for more effective targeting of the enzyme for the treatment of Alzheimer’s disease. Understanding how natural variation influences DNA binding by transcription factors will facilitate the development of molecular diagnostic tools for rare genetic diseases

The Solution

Our group employs molecular modelling and simulation approaches to investigate biomolecular recognition and understanding the underlying physics of the interaction. We employ approaches ranging from structural prediction, computational residue scanning, molecular dynamics simulations, enhanced sampling simulations, and binding free energy calculations

The Outcome

Resources at the Pawsey Centre are crucial to facilitate the outcomes of this project. The simulations we perform involve calculations between a very large number of atoms (typically approaching or exceeding 100,000 atoms), precluding the use of desktop computing resources. Additionally, as we are frequently interested in a combinatorial range of complexes, being able to perform many simulations in parallel is crucial for timely outcomes. The general availability of Pawsey’s new GPU cluster, Topaz, will be valuable for progressing this work throughout 2020.

List of Publications

Isabel A. Hemming Olivier Clément Ivan E. Gladwyn‐Ng Hayley D. Cullen Han Leng Ng Heng B. See Linh Ngo Daniela Ulgiati Kevin D.G. Pfleger Mark Agostino Julian I‐T. Heng. Disease‐associated missense variants in ZBTB18 disrupt DNA binding and impair the development of neurons within the embryonic cerebral cortex. Human Mutation, 2019, v40, p1841-1855.