> Corry Group

Voltage-Gated Sodium Channels

Sodium channels are responsible for initiating electrical activity in nerve and muscle cells. They allow charged Na+ ions to rapidly flow into cells in reponse to small depolarising signals, thereby staing the short lived electrical impiulse known as the action potential. Local anaesthetic, anti-epileptic and anti-arrythmic drugs act by blocking these channels, thereby diminishing electrical activity in nerve and muscle. We are interested in better undersatnding both fundamental and applied aspects of the function of these proteins. How do they respnd to different stimulus? How do they let just Na+ ions through while blocking other ion types? Can we design more targetted drugs that inhibit just one of the multiple channel subtypes found in the body?

Key publications:
Locating the route of entry and binding sites of benzocaine and phenytoin in a bacterial voltage gated sodium channel. PLoS Comp. Biol. , 10(7): e1003688. Online manuscript
Mechanism of ion permeation and selectivity in a voltage gated sodium channel. J Am Chem Soc, 134: 1840-1846, 2012. online manuscript

Mechanisms of ion selectivity

Many biological molecules, including channels, transporters, enzymes, macrocycles and DNA selectively bind or transport ions. Although ion selectivity is critical to the function of most such molecules, the physical mechanisms by which it arises are not well understood. While we are particularly interested in understanding the origins of ion selectivity in biological channels, many of the principles involved in these proteins apply in other cases as well. By comparing the results of detailed simulations on a range of systems and developing model systems in which different mechanisms can be teased out we are not only explaining selectivity in each particular case, but also slowly gaining an appreciation of the many ways selective binding can arise and the conditions in which each is important. Although fundamental in nature, this research helps to explain the functioning of a number of critical molecules in human biology and lays the foundation for future innovation in biomedical research.

Collaborators: Dylan Jayatilaka, UWA
Key publications:
Mechanism of ion permeation and selectivity in a voltage gated sodium channel. J Am Chem Soc, 134: 1840-1846, 2012. online manuscript
Mapping the Importance of Four Factors in Creating Monovalent Ion Selectivity in Biological Molecules. Biophys. J. 100: 60-69, 2011. pdf , supp info
The predominant role of coordination number in potassium channel selectivity. Biophys. J. 93:2635-2643, 2007. pdf
Mechanisms of valence selectivity in biological ion channels. Cellular and Molecular Life Sciences. 63: 301-315, 2006. pdf

Monitoring ion channel gating

Conformation changes are critical to the function of many proteins yet are difficult characterise at an atomic level. To better understand these structural alterations we are combining experimental methods with simulation in order to characterise protein states that are hard to study by other methods. We are also using modern free energy simulation methods to map out the structural changes of a range of channel forming proteins. We are particularly intersted in the family of bacterial mechanosensitive channels that form safety valves that protect cells from hypo-osmotic shock, opening a wide pore under membrane tension to relieve excessive turgor pressure within the cell. By combining fluorescence measurements with molecular dynamics and coarse grained simualtions we have been able to propose a structure of the open state of the protein and to examine the functions of various protein domains.

Collaborators: Boris Martinac, VCCRI
Key publications:
An improved open channel structure of MscL determined from FRET confocal microscopy and simulation. J Gen Physiol. 136: 483-494, 2010. pdf
Ion conduction in ligand gated ion channels: Brownian dynamics studies of four recent crystal structures. Biophys. J. 98: 404-411, 2010. pdf
An energy efficient gating mechanism in the acetylcholine receptor channel suggested by molecular and Brownian dynamics. Biophys. J. 90: 799-810, 2006. pdf

Desalination Membranes

Desalination of sea water via reverse osmosis is an attractive means of obtaining potable water, but one of its main drawbacks is the energy and cost required to force the water through semipermeable membranes that block the passage of the salt. The energy costs could be reduced, however, if new membranes could be developed with continuous pores that offer less resistance to water. Many narrow biological pores do just this: a pore of a given radius surrounded by non-polar atoms can allow for water to pass, but impede the passage of ions. Research in the group has shown that membranes formed from synthetic pores that mimic these biological channels, such as carbon nanotubes, can be used in desalination. Not only has this work shown that such membranes could significantly reduce the energy cost of reverse osmosis, it has determined the exact dimensions of the pores that are required and the effect of chemical functionalisation.

Collaborators: Mainak Majumder, Monash
                       Andrea Schäfer, Edinburgh
Key publications:
Water and ion transport through functionalised carbon nanotubes: implications for desalination technology. Energy Env Sci, 4: 751-759, 2011. pdf
Designing carbon nanotube membranes for efficient water desalination. J. Phys. Chem. B. 112:1427-1434. 2008. pdf Cover picture
An intrinsic ion selectivity of narrow hydrophobic pores. J. Phys. Chem. B. 113: 7642-7649, 2009. pdf

FRET methodology

Förster resonance energy transfer is becoming increasingly widely utilized to measure the proximity of molecules, structural changes within macromolecules, as a signal of biochemical events or as a sensor of local conditions. We are interested in using the method to gain quantitative structural information and in deveoping ways to make the measurement of FRET efficiencies more precise. Interpreting FRET methods can also be complicated due to the presence of multiple fluorophores with unknown orientations. We are thus developing ways to aid this interpretation with numerical analysis and molecular simulation.

Key publications:
A flexible approach to the calculation of resonance energy transfer efficiency between multiple donors and acceptors in complex geometries. Biophys. J. 89:3822-3836, 2005. pdf
Determination of the orientational distribution and orientation factor for transfer between membrane bound fluorophores using a confocal microscope. Biophys. J. 91:1032-1045, 2006. pdf
Quantitative FRET efficiency measurements using simultaneous spectral unmixing of excitation and emission spectra. J. Biomed. Optics., 8: 026024, 2013. online manuscript

Dynamics in organic crystals

Molecular dynamics simulations provide a way to invetigate the motions of atoms in crystals as the motion of individual atoms and molecules can be monitored. We are interested in studying the atomic vibrations and reorientations of part or all of a molecule that affect bulk properties of the material, and understanding disorder that affects structure refinement. We are particularly interested in porous crystalline structures, examining the behaviour of guest molecules within porous hosts using simulation strategies with the long term aim of finding materials that can selectively transport guests for application in gas separation and storage.

Collaborators: Mark Spackman, UWA
                      Birger Dittrich Göttingen
Key publications:
Molecular dynamics simulations of structure and dynamics of organic molecular crystals. Phys Chem Chem Phys, 45: 14916-14929, 2010. pdf
Temperature dependence of rotational disorder in a non-standard amino acid from X-ray crystallography and molecular dynamics simulation, Phys. Chem. Chem. Phys., 11: 2601-209, 2009. pdf
Simulations of guest transport in clathrates of Dianin's compound and hydroquinone. Chem Eur J, 19: 2676–2684, 2013. online manuscript
 
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