It was believed that a protein sequence would define a single, well-defined three-dimensional structure. Using x-ray crystallography, we have discovered that the protein CLIC1 can adopt several well-defined structures. Along with the concurrent discovery of two other such proteins, this has led to the concept of metamorphic proteins. Our currently we are focussing on understanding the structure, function and evolution of the CLIC protein family. In particular, we aim to determine the structure of the intergral membrane state of the CLIC ion channel.
Does quantum mechanics play a non-trivial role in biology?
Proteins were assumed to function via classical physics with quantum effects playing trivial roles. In collaboration with Greg Scholes (U. Toronto) we have shown that certain algal light harvesting proteins show spectroscopic signatures of long-lived quantum coherence under near physicological conditions. Along with parallel discoveries, this has led to intense research activity aimed at determining the physical mechanism behind the observed long-lived oscillations in the 2D electronic spectra and whether quantum electronic coherence plays a role in photosynthetic light harvesting.
How do molecular machines work?
Protein machines function as motors, but there is no satisfactory explanation as to how they transduce energy. We are part of an international group to try and build a protein based molecular motor from non-motor components (Heiner Linke, Lund University, Dek Woolfson, Bristol University, Nancy Forde and Martin Zuckermann, Simon Fraser University, Vancouver, Beth Bromley Durham University, Gerhard Blab, Utrecht University). The aim is to test whether protein motors work by rectifying noise (ratchet). We have designed several candidate motors and we are currently building them using molecular biology and semi-synthetic approaches.
How do proteins know where they are in cells?
The interior of any cell is far from homogeneous. What produces the patterns of protein distributions? Is there a map? Using the concept of Turing patterns, we are modelling protein systems that determine the site of cell division. We have identified a minimal set of biochemical reactions that via a reaction-diffusion mechanism create stable patterns that account for observed cell division. The model relates cell geometry to protein distributions.
Controlling membrane remodelling in mammalian cells:
We are establishing the link between CLICs, ERM proteins, Rho GTPases and the cortical actin cytoskeleton. In collaboration with Till Boecking (UNSW), we are developing single molecular approaches to probe the interactions of these proteins in artificial systems and cells. The assembly of cellular complexes may involve similar mechanisms to those we are modelling for cell division.
Past Research Interests
- The b-sheet. We have analysed the physical interactions that affect the correlations of amino acids within an antiparallel beta sheet. We have also identified the physical mechanism responsible for the shear and twist of beta-sheets.
- Archeal Proteins. We are studying proteins from the archea Methanococcus janaaschii. In particular, we are looking at chaperonin and prefoldin.
- Functional genomics. We are looking at how closely related functional groups between proteins are within domains
- Thermostability of proteins. This involved the simulation of thermal agitation using X-PLOR.
- Human Plasminogen Activator Inhibitor 2 (PAI-2). PAI-2 is a serpin that finds, binds to and inhibits Human Plasminogen. During the process of inhibition, the serpin undergoes an incredible conformational change, which involves inserting a loop into a beta sheet as an extra strand. We have determined the crystal structure of PAI-2 in the stressed state (image, PDB entry: 1BY7).
- Light harvesting membrane complexes pf cryptophytes. We have determined the crystal structure of phycoerythrin 545. This protein holds several tetrapyrrole chromophores which trap photons. (image, PDB entry: 1QGW, on-line article).
- Rubisco. Rubisco is the most abundant protein in plants. Based on the structure, we have postulated a mechanism for closing and a mechanism for catalysis. (image, PDB entry: 1EJ7).