Dr Simon Connell

Profile

PhD Biophysics (Portsmouth 1999), PDRA Physikalische-Chemie, Helmholtz-Zentrum, Berlin (1999), PDRA School of Pharmacy, Nottingham (99-01), PDRA School of Physics and Astronomy, Leeds (2001-05), Senior Research Fellow (2005-10), Lecturer (2010-17), Associate Professor (2017- )

Research interests

My research primarily concerns the development and application of Atomic Force Microscopy (AFM) and related techniques to areas of biological physics and soft matter physics, and to understand fundamental properties of matter by characterising structure, mechanics and dynamics at the nanoscale. This is aided with the use of complementary characterisation techniques such as AFM with directly correlated time-resolved scanning confocal fluorescence microscopy (FLIM); Quartz-Crystal Microbalance with Dissipation (QCM-D) to measure surface deposition; magnetic tweezers with high speed cameras for passive and active micro-rheology of soft gels and solutions, Langmuir trough for characterisation of interfacial films and surface deposition, and differential scanning calorimetry (DSC) for the thermal response. I have a particular interest in the study of soft matter dynamics at the nanoscale using Fast Scanning AFM. I also manage the Leeds EPSRC AFM Facility. Current research projects fall into three main areas:

1.    Lipid bilayers. 

The outer plasma membrane of any cell, and all interior membranes which compartmentalise the cell, consist of amphiphilic molecules called lipids which spontaneously self-assemble into a bilayer. This fluid lamellar phase constitutes an impermeable chemical barrier which is sandwiched between the more structural elements of the cell wall, the cytoskeleton and the extra-cellular matrix. The membrane is home to a large proportion of all cell proteins, and an area of interest is how the properties of the membrane affect the functioning of trans-membrane proteins, and vice-versa. For many years the membrane was considered as a passive flexible bag that fulfils its barrier function and into which the proteins could be located, but it is now known that biomembranes have their own incredibly rich behaviour, in terms of phase structure, curvature and leaflet symmetry/asymmetry. We are particularly interested in the relevance of phase separation to the function of cell; the existence of so-called ‘lipid’ rafts; the kinetics of phase separation and the dynamics of micro and nano-domains in various environments; the mode of action of drugs and peptides that affect the membrane, and the influence of trans-membrane proteins on membrane structure and function. A new project aims to redesign a proven anti-cancer peptide by understanding the mechanism behind its specificity and thereby increase its efficiency and target other cancers.

2.    Fibrinogen and blood clotting

Fibrinogen is a soluble protein monomer which exist in high concentration in the blood, which upon injury is converted by thrombin-mediated proteolysis into fibrin, a form which polymerises into long fibres around 100 nm in diameter. After growth by lateral assembly and cross-linking with neighbouring fibres a network is rapidly formed, forming a strong and flexible structure for the blood clot. This is the basis of blood coagulation. Fibrin is a visco-elastic material with remarkable biomechanical properties, including an incredible extensibility of over 300%. We study this mechanical behaviour across all-length scales, from the single molecule, up through single-fibres with AFM pulling and stretching experiments, to the micro-scale with magnetic tweezers equipped with high speed cameras. Molecular structure and clot architecture are determined using atomic force and electron microscopy, and overall clot growth and aspects of internal fibre architecture are derived from optical light scattering, spectroscopy and confocal scanning fluorescence microscopy. With these powerful tools at our disposal the biochemical basis for the final clot can be determined by altering the protein sequence in systematic fashion (post-translational modification) to unravel the inner workings of coagulation. Disease states and potential therapeutic interventions can also been studied in detail. Recent work has revealed a new fibrin structure at the surface of a clot, a fibrin sheet which seals the clot and prevents microbial infection at the very earliest stage of coagulation.

3.    Nano-mechanics of natural and synthetic polymers

We are developing and refining our methods for quantifying mechanical properties of materials in the range 1 kPa – 10 GPa, at length scales of 100 m down to < 10 nm using various AFM force mapping techniques. Combining the measurements with temperature control allows us to fully map the structure of complex materials and determine thermal transitions such as melting point or glass transitions of individual inclusions or phases within phase-separated materials. Current projects include determination of the internal mechanical properties of individual nanometre sized thermos-responsive microgel particles vs temperature and crosslink density; the study of complex food polymer phase structure; nanometre determination of components in carbohydrates with correlated micro-RAMAN mapping; measurement of thin interphases in a three-component polymer blend, and to unravel the mechanical properties of plant cell walls, and the influence of the individual components such as cellulose, callose and xylo-glucans.

Research groups and institutes

• Molecular and Nanoscale Physics