Corry Lab

Lipid Regulation of Ion Channels

The plasma membrane was traditionally considered a passive barrier, the background in which transmembrane proteins are embedded. However, growing evidence indicates that the lipid components of the membrane actively contribute to regulating the function of these proteins, including ion channels. The molecular mechanisms by which lipid modulation occurs and whether this can be exploited to tailor ion channel function has yet to be fully explored.

We aim to simulations and collaborative experiments to answer questions such as - Can we predict the binding sites of key lipid species, such as phosophoinositides/PIPs? Do the lipids interact with channels via their acyl tails or headgroups? How do lipids influence the activity of force-sensing proteins, such as OSCA/TMEM63 and Piezo? Are there potential therapeutic applications of lipid-mimicking molecules to treat ion channel-related diseases?

Mechanosensitive Ion Channels

Touch, hearing, and blood pressure control require mechanically-gated Piezo ion channels that convert mechanical stimuli into electrical currents. Piezo channels were recently identified as essential eukaryotic mechanically-gated ion channels involved in touch, yet how they respond to physical forces remains poorly understood, and many questions remain. Are they a molecular sensor of membrane curvature? What does the open state of Piezo 1 look like? How and why do these proteins cooperate? Can we explain diseases associated with malfunction of Piezo?

Thermodiffusion

Much like concentration gradients, temperature gradients can induce the movement of particle within a solution. This effect, known as thermodiffusion or thermophoresis, is a peculiar phenomenon with no fully accepted physical explanation. A particle can either move towards warmer areas or colder areas depending on the average temperature of the solution. In this project, we use molecular dynamics simulations to better understand the physical basis of this phenomenon and to explore how it can be maximised for applications such as the filtration of water.

Malaria Transporters

The increasing incidence of multi drug resistant malaria across the globe threatens the resurgence of one of humanities most devastating infectious disease. This resistance is often mediated by membrane transporter proteins, thwarting chemotheraputic interventions by transporting the drug molecules away from their site of action. But these membrane transporters may be the Malaria parasite's undoing; it's parasitic lifecycle has streamlined its transportome to a limited set of essential proteins that are ripe for molecular targeting. Projects in this area will seek to answer questions such as what is the structural basis of Malaria's multi drug resistance? Can we predict which drugs will be harder to evolve resistance to? How do drugs interact with their targets, and is it possible to design drug regimes which create evolutionary dead ends.

Molecular mechanisms of innate immunity

Viruses are detected by the innate immune system when fragments of their DNA or RNA bind to recognition toll-like receptors. Mutations in these receptors that either lead to either overactive or underactive immune systems can be responsible for debilitating autoimmune diseases or severe COVID-19 and other viral disease. But, how these proteins work at the molecular level is still not clear. Our research examines the fundamental recognition and activation mechanisms of these receptors as well as how they can be targeted by novel therapeutics.

Voltage-Gated Sodium Channels

Sodium channels are responsible for initiating electricalactivity in nerve and muscle cells. Malfunction can lead to epilepsy, cardiac arrhythmias and pain conditions, and these proteins are the target of many anaesthetic, anti-epileptic and anti-arrhythmic drugs. But there are still many unanswered questions.Can we design new sodium channel inhibitors to treat chronic pain? What are the molecular mechanisms of channel inactivation? Can we explain the molecular origins of epilepsy? How can these channels let just sodium through while blocking other ion types?