... understanding life in molecular detail

Dr George Heath

High-Speed Atomic Force Microscopy; Membrane Proteins; Lipid Membranes; Biophysics


My research interests are focused on developing techniques to study the structure and dynamics of biomolecules at previously inaccessible time and spatial resolutions using atomic force microscopy. In doing this we aim use physics and physical tools to better understand biological processes related to health and disease.

Current major projects include:
  • Developing high-speed atomic force microscopy methods for microseconds and sub-nm resolution
  • Conformational dynamics of TRPC ion channels in response to small molecules
  • Force response and structural dynamics of mechanosensitive ion channels

The rapid expansion in the structural understanding of membrane proteins through recent progress in electron microscopy and X-ray crystallography is leading to an ever-greater need for techniques which give high temporal resolution dynamics. High-Speed Atomic Force Microscopy (HS-AFM) provides unprecedented real-space and real-time visualisation of biological molecules (100 ms temporal resolution). We have recently developed HS-AFM to increase the already pioneering 100ms time resolution to 10μs. This 10,000-fold leap in acquisition rate is achieved by no longer scanning the surface with a tip, but by holding it at a single point of interest and studying the dynamics of molecules underneath. This offers the capability to directly study how protein dynamics can be modulated by various small molecules and stimuli to inform the pursuit of therapeutics.

 

Pushing and imaging mechanosensitive channels

Mechanosensitive channels are found throughout all kingdoms of life acting as sensors for a number of systems including touch, hearing, gravity, osmotic pressure and cardiovascular regulation. Embedded within lipid membranes, these pressure sensitive channels sense and open upon specific mechanical stimuli allowing certain molecules to enter or exit the cells. In humans they are vital for many physiological functions and a number of specific genetic mutations within these channels have been implicated in several diseases. On the other hand, bacteria use this class of channels to regulate their internal turgor pressure in response to rapid changes in osmotic pressure. Despite their fundamental importance, the molecular mechanism of how these channels respond to membrane tension is not well understood. Developing an understanding of these mechanisms will help resolve the molecular basis of mechanical sensing and its role in ion channel regulation and cell physiology. Targeting these channels will provide us with essential molecular and mechanical tools to fight antimicrobial resistant bacteria and channel associated diseases in humans. We aim to utilize HS-AFM to monitor conformational dynamics of single membrane protein channels in real-time at the nanoscale and in response to different forces.

 

TRPC ion channel structural dynamics

Transient receptor potential canonical (TRPC) 1/4/5 channels are found in many cell types including the nervous and cardiovascular systems, where they form nonselective cationic channels with high calcium permeability. Structural and mechanical knowledge of these channels is rapidly evolving, suggesting TRPC1/4/5 assemblies play crucial roles in human physiology and pathology, and consequently are potential drug targets for renal failure, anxiety, cancer, pain, and cardiac remodeling. Our goal is to study the dynamic structural changes in TRPC1/4/5 assemblies reconstituted into near-native membranes as a function of modulators by high speed AFM. The mechanisms we aim to uncover will not only be applicable to TRPC but also to all other TRP and heteromeric ion channels for which structural information is scarce and will therefore have important implications for general channel physiology and pharmacology.

Detailed research programme                  Close ▲
GHe.jpg

University Academic Fellow

PhD (Physics, Leeds) 2010-2014
Postdoc (Biology, Leeds) 2014-2017
Postdoc (Cornell) 2017-2019

8.52 EC Stoner building
School of Physics
g.r.heath@leeds.ac.uk

https://eps.leeds.ac.uk/physics/staff/6132/dr-george-heath

Selected Publications

  1. Heath, G.R., Scheuring, S. High-speed AFM height spectroscopy reveals µs-dynamics of unlabeled biomolecules. Nat Commun 9, 4983 (2018)

  2. Heath, G. R. & Scheuring, S. Advances in high-speed atomic force microscopy (HS-AFM) reveal dynamics of transmembrane channels and transporters. Curr. Opin. Struct. Biol. 57, 93–102 (2019).

  3. Heath, G. R. et al. Multilayered Lipid Membrane Stacks for Biocatalysis Using Membrane Enzymes. Adv. Funct. Mater. 27, (2017).

  4. Heath, G. R., Roth, J., Connell, S. D. & Evans, S. D. Diffusion in low-dimensional lipid membranes. Nano Lett. 14, 5984–5988 (2014).