BIOLOGICAL PHYSICS (BioP)
Research in the Biological Physics Group employs a range of techniques, both theoretical and experimental, to probe biological and soft -matter systems to reveal the physics that governs their behaviour.
Current research in this group includes
- Imaging, probing & manipulation, from molecules to cells
- Materials & magnetism for biosensing and therapy
- Theory & Modelling
Resolving the structure of a single biological molecule
Researchers at the London Centre for Nanotechnology have determined the structure of DNA from measurements on a single molecule, and found that this structure is not as regular as one might think, as they report in the journal Small.
Our life depends on molecular machinery that is continuously at work in our bodies. The structure of these nanometre-scale machines is thus at the heart of our understanding of health and disease. This is very apparent in the case of the Watson-Crick DNA double-helix structure, which has been the key to understanding how genetic information is stored and passed on.
Watson and Crick’s discovery was based on diffraction of X-rays by millions of ordered and aligned DNA molecules. This method is extremely powerful and still used today – in a more evolved form – to determine the structure of biological molecules. It has the important drawbacks, however, that it only provides static, averaged pictures of molecular structures and that it relies on the accurate ordering and alignment of many molecules. This process, called crystallisation, can prove very challenging.
Building on previous work in Dr Bart Hoogenboom’s research group at the London Centre for Nanotechnology, and in collaboration with the National Physical Laboratory, first author Alice Pyne has applied “soft-touch” atomic force microscopy to large, irregularly arranged and individual DNA molecules. In this form of microscopy, a miniature probe is used to feel the surface of the molecules one by one, rather than seeing them.
To demonstrate the power of their method, Pyne, Hoogenboom and collaborators have measured the structure of a single DNA molecule, finding on average good agreement with the structure as it has been known since Watson and Crick. Strikingly, however, the single-molecule images also reveal significant variations in the depths of grooves in the double helix structure.
While the origin of the observed variations is not yet fully understood, it is known that these grooves act as keyways for proteins (molecular keys) that determine to which extent a gene is expressed in a living cell. The observation of variations in these keyways may thus help us to determine the mechanisms by which living cells promote and suppress the use of genetic information stored in their DNA.
Journal link: Single-molecule reconstruction of oligonucleotide secondary structure by atomic force microscopy, Small (2014), DOI: 10.1002/smll.201400265, early view on-line version
Figure: An image of the DNA double helix structure taken with the AFM, with the Watson-Crick DNA structure overlaid (purple and blue).
Holes ripped in bacteria to prevent infection
There is an urgent need to find new antibiotics as bacteria are constantly evolving and steadily becoming resistant to the current arsenal used by doctors around the world. A key question is whether it is possible to create better anti-infective agents using design principles rather than by trial and error. Antimicrobial peptides are short protein fragments that have been suggested as such future alternatives to current antibiotics. They identify bacteria and disrupt their membrane structure, thus ultimately killing the bacteria.
A research team consisting of scientists from the London Centre for Nanotechnology (LCN), National Physical Laboratory, University of Edinburgh, University of Oxford, Freie Universität Berlin and IBM, have now used a combination of nanoscale imaging, computer simulation and de novo protein design to reveal a new mechanism of membrane disruption by antimicrobial peptides.
The results uncover a dynamic process whereby peptides form tiny pores, only a few nanometres across, which subsequently expand until they eventually reach the point of complete membrane disintegration. The direct observation of these processes adds to the prevailing models regarding membrane perforation by antimicrobial peptides, revealing a molecular mechanism of active pore expansion.
This offers a physical basis for bacterial membrane disruption which may be useful for drug developers when designing new medicines to combat infections.
Journal link: Nanoscale imaging reveals laterally expanding antimicrobial pores in lipid bilayers, Proc. Nat. Acad. Sci. USA 2013 ; published ahead of print May 13, 2013,doi:10.1073/pnas.1222824110
Figure: Time-lapse atomic force microscopy showing the formation and growth of pores in biological model membranes by antimicrobial peptides.