Intersect provides HPC resources to further knowledge in the area of human disease identification and treatment
Hear from Professor Brian Smith, Dean and Head of the School of Molecular Sciences at La Trobe University, and Director of the La Trobe Institute for Molecular Science (LIMS) on how Intersect is assisting him to achieve better research outcomes.
The Smith Lab within the La Trobe Institute for Molecular Science at La Trobe University, Bundoora, employs molecular dynamics software to study the interactions between proteins and drugs in the development of new compounds to treat significant human diseases.
The software used in the Smith Lab is primarily the GROMACS simulation suite. This software suite capitalises on the performance of Graphics Processing Units (GPUs), which is central to the analysis and collection of data within the lab. The systems of interest are pretty large (50-500 thousand atoms), that are run for long simulation times (1-5 microseconds), and each simulation is typically repeated 5-10 times.
While these simulations involve simple Newtonian mechanics, the calculations require vast amounts of aggregated computer power. This resource is provided by NCI (National Computational Infrastructure), a provision facilitated by La Trobe University’s partnership with Intersect Australia. Intersect provides their member universities (such as La Trobe University) with allocated access to HPC resources delivered by NCI.
Several projects currently being conducted in the Smith Lab have been assisted by this provision, with a brief outline of each project below.
Diabetes is a significant contributor to the global burden of disease. The current treatment for Type-1 diabetes (T1D) and late-stage Type-2 diabetes (T2D) is the subcutaneous injection of insulin. Worldwide, more than 200 million individuals require daily insulin injections. Despite this life-saving treatment, many patients will suffer from diabetes-related illnesses, including cardiovascular and kidney disease. There is an urgent need to develop new forms of insulin that are faster acting and are more stable, obviating the need for cold storage. This work focuses on using computational tools, primarily molecular dynamics (MD), to investigate the interaction of insulin with its cognate receptor, the insulin receptor (IR).
The mineralocorticoid receptor (MR) plays a vital role in critical physiological progress such as water-electrolyte homeostasis and blood pressure regulation. In collaboration with Prof Peter Fuller from the Hudson Institute of Medical Research, we investigate how receptors from different species respond differently to the same ligand. Recently, we identified a single-point mutation in the MR that converts an agonist ligand to an antagonist. In another species, the same ligand converts from an antagonist into an agonist. From an understanding of ligand diorism, it should be possible to design new therapeutics against the nuclear receptor family proteins with a specific function.
Ion channels mediate ionic diffusion across cell membranes. Orchestrated ion channel activity propagates the electrical signals that drive the human central nervous system and vital organs and underpins neurological, cardiac, endocrine, and essential developmental and homeostatic functions. Potassium channels, of which the human genome encodes over eighty, fine-tune the membrane potential, participate in cascades that regulate local Ca2+ levels, facilitate cellular messaging, and are responsible for adjusting cell volume required to commit to cell cycle progression. Thus, their actions are directly or indirectly intrinsic to the signal transduction pathways that control cell division and apoptosis, activation of immune cells, and regulation of cell function. Naturally occurring mutations impairing the ability to gate K+ currents are linked to a broad spectrum of diseases (including heart arrhythmia, diabetes, and others), and recent investigations have decisively linked anomalous expression of native K+ channels in cancer cells to invasiveness and malignancy of brain, colon and breast cancers. In collaboration with Dr. Jacqui Gulbis, WEHI, aims to uncover the mechanism of gating and conduction in one of these channels, KirBac3.1.
Bim is a key protein that triggers the process of programmed cell death, apoptosis. Small peptides from a small region of this protein, the BH3 domain, with a hydrocarbon linkage have been shown to efficiently penetrate the cell membrane, whereas the native peptide does not. In this project, we have been exploring the mechanism of BimBH3 peptide membrane penetration.
~ Professor Brian Smith
The successful completion and publication of these research projects rely on continued access to HPC services from Intersect. This collaboration between Intersect and Professor Brian Smith’s laboratory at La Trobe University makes a significant contribution to the furthering of knowledge in the area of human disease identification and treatment.