Computational Structural Investigation of Molecular Interactions in Cancer Biology and Neurological DisordersThis 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 investigatorMark Agostino Mark.Agostino@curtin.edu.au
Area of scienceBiomolecular modelling, Health, molecular dynamics
Systems usedMagnus and Zeus
Applications usedGROMACS, AMBER, PLUMED
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
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
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.