Current Research Projects

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?


Collaborators: Boris Martinac, VCCRI ; Charles Cox, VCCRI

Key publications:
YC Lin, A Buyan, B Corry. Computational studies of Piezo1 yield insights into key lipid-protein interactions, channel activation and agonist binding. Biophys. Rev. In press, 2021. Online manuscript
A Buyan, CD Cox, J Barnoud, J Li, HSM Chan, B Martinac, SJ Marrink, B Corry. Piezo1 forms specific, functionally important interactions with phosphoinositides and cholesterol. Biophys J. 119: 1682-1697, 2020. Online manuscript | Commentary

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.


Collaborators: Juan Felipe Torres Alvarez, CECS

Key publications:
A Hutchinson, JF Torres, B Corry. Modelling thermodiffusion in aqueous sodium chloride solutions - which water model is best? J. Chem . Phys. In press, 2022. Online manuscript

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.


Collaborators: Adele Lehane, RSB ; Sarah Shafik, RSB

Key publications:
S Shafik, S Richards, B Corry and R Martin. Mechanistic basis for multidrug resistance and collateral drug sensitivity conferred on the malaria parasite by polymorphisms in PfMDR1 and PfCRT. PLoS Biology. In press, 2022. Online manuscript

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.


Collaborators: Carola Vinuesa, JCSMR ; Michael Gantier, Hudson Research Institute ; Julia Ellyard, JCSMR

Key publications:
Grant J. Brown, ... Josiah Bones, ... Ben Corry, Michael P. Gantier, Vicki Athanasopoulos and Carola G. Vinuesa. TLR7 gain-of-functiongenetic variation causes human lupus. Nature. In press, 2022. Online manuscript

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?


Key publications:
E Tao, B Corry. Characterising fenestration size in sodium channel subtypes and their accessibility to inhibitors. Biophys. J. 121: 193-206, 2022. Online manuscript | Blogpost
A Buyan, A Whitfield, B Corry. Binding of Local Anaesthetics and Anti-Epileptics to the inactivated human sodium channel Nav1.4. Biophys. J. 120: 5553, 2021. Online manuscript
Protonation state of inhibitors determines interaction sites within voltage-gated sodium channels. Proc. Natl. Acad. Sci. USA 10.1073/pnas.1714131115, 2018. Online manuscript
Physical basis of specificity and delayed binding of a subtype selective sodium channel inhibitor. Scientific Reports 8:1356, 2018. Online manuscript
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

SARS-CoV2 Spike Protein

We believe that SARS-CoV-2 jumped to humans from animal sources and the next deadly human coronavirus will likely come from an animal source. Despite large and rapidly increasing genetic databases of human and animal coronavirus genome sequences we currently lack the ability to judge which of these viruses will be dangerous to humans other than via simple genetic similarities. This project seeks to address this through molecular dynamic simulations and sequence analysis, with applications in assessing the relative risk of coronaviruses circulating in wild and domestic animal populations.