Watching molecules wobble

We are interested in the structure and motion of biomolecules, and how these relate to their functional and evolutionary roles in biology. We do everything from developing techniques for in silico investigation of biomolecular structure and interactions, to applying these in diverse areas ranging from drug development to fathoming the earliest stages of protein evolution. While much of our research is at a fundamental level, we're not averse to working on things that might be useful in the near(ish) future. The things we're most excited about at the moment include:

Automated parameterisation of atomic-level models

While molecular dynamics simulations are a powerful way to probe molecular structure and motion at an atomic level of detail, they have traditionally been highly reductionist, with a typical atomic-level simulation system comprising a single protein molecule surrounded by water - a far cry from cellular conditions. One reason for this austerity is that reliable parameter sets are only available for the most common biomolecules, and manual parameterisation of new molecules is error-prone, tedious and slow. We are working with the group of Alan Mark (University of Queensland) to develop a high-throughput framework for automated parameter assignment and optimisation that will generate reliable parameter sets for almost any biomolecule imaginable.

Development of supra-atomic lipid models for multi-scale simulation

To allow exploration of the behaviour of biological systems larger spatial and temporal scales, we are developing supra-atomic ("coarse-grained") lipid models together with Assist. Prof. Sereina Riniker and Emiritus Prof. Wilfred van Gunsteren (ETH Zurich). These models will be compatible with the GROMOS supra-molecular solvent models and atomic-level solvent and biomolecule models, enabling multi-scale simulation of large, complex biological systems for biologically relevant timescales. Additionally, because they will be polarisable, they will be responsive to the local electronic environment in a way that many coarse-grained models are not.

Structural phylogenetics

We are working with Assoc. Prof. Anthony Poole, University of Canterbury on applying molecular dynamics simulations to evolutionary biology to probe deep evolutionary relationships and to recategorise the protein structure universe. Sophisticated phylogenetic methods have been developed to exploit the avalanche of sequence data currently being generated, but these fail at long evolutionary distances, as the similarities become too low - the so-called "twilight zone". We are taking advantage of the fact that protein structure is better conserved than sequence, along with the recent exponential growth of structural information for extant species and the capacity of molecular dynamics simulations to explore structural flexibility to provide new ways of examining relationships between protein structures and of studying the earliest events in the history of life, where evolutionary signal is scant.

Where proteins and membranes meet

Characterisation of protein-membrane interactions is vital due to their central importance in cellular metabolism and signal transduction, yet they are notoriously demanding to investigate experimentally due to the difficulty in including lipid phases in most techniques for studying protein structure and function. We have a number of ongoing projects involving the use of molecular dynamics simulations to probe protein- or peptide-membrane interactions for a range of different systems, including the novel cancer therapeutic target phosphoinositide 3-kinase (PI3Kα, with Dr Jack Flanagan, Auckland Cancer Research Institute and Prof. Peter Shepherd, University of Auckland); membrane-penetrating anti-microbial and anti-cancer peptides (with Viji Sarojini, University of Auckland), and the anti-fungal cytochrome P450 (with Assoc. Prof. Joel Tyndall, University of Otago).

Coupling NMR data with MD simulations

As well as using NMR data, when available, to validate or bias our simulations, we work on development of methodology for combining NMR data with molecular dynamics simulations. A key recent achievement (Lukas Wirz, former PhD student) is the development and implementation of novel means of biasing molecular dynamics simulations to fit experimentally measured NMR residual dipolar couplings into the GROMOS biomolecular simulation software, for which we form part of the development team. We also have an ongoing collaboration with Assist. Prof. Lorna Smith (University of Oxford) in this area.

Miscellaneous ...

Other things we are working on include, but are not limited to, developing a method for enhanced conformational sampling by adaptive swelling of the protein backbone (with Deborah Crittenden, University of Canterbury), modelling the three-dimensional chromosome structure at different points in the cell cycle (with Justin O'Sullivan, Liggins Institute), determining the contribution of protein heat capacity to enzyme function (with Vic Arcus, University of Waikato), and characterising the interaction of milk proteins with different oil/water interfaces (with Kate McGrath, MacDiarmid Institute) and designing self-assembling lanthanide based amphiphiles for biosensor applications (e.g. nerve gas detection) (with Dr Jon Kitchen, University of Southampton).