Computational Biology

The transition mode of the enzyme PHBH modelled with QM/MM
The transition mode of the enzyme PHBH modelled with QM/MM

The Computational Biology theme of the department brings together several activities in the life sciences. We have a particular strength in computational structural biology, and host the Instruct computational centre. We host the core group for CCP4 in macromolecular crystallography, and host a similar group for CCP-EM (link opens in a new window) in biological electron cryo-microscopy. The PiMS (link opens in a new window) project is developing an information management system for protein production and crystallisation. We are active in biomolecular simulation, providing support for CCP-BioSim (link opens in a new window) and collaborating with experimental groups in STFC in a study of epidermal growth factor receptor. Finally, we lead a new theme in data-intensive biology, with a particular focus on next generation sequencing.

For more information about the Computational Biology team please contact Dr Martyn Winn. A list of current staff can be found on the staff pages.

Current projects

Atomistic MD simulations

CHO cells with cytosolic GFP and extracellular EGF-Alexa546
CHO cells with cytosolic GFP and extracellular EGF-Alexa546

MD simulations help us understand the dynamical properties of biological systems at the molecular, fully atomistic level. Projects we are currently involved in are described in the following.

We investigate membrane receptors, e.g. the epidermal growth factor receptor (EGFR) and ErbB family. ErbB receptors transduct signals from the cell surface through the membrane to the cytosolic tyrosine kinase where the signal is propagated in a cascade further down to launch certain cell processes. The ErbB receptor family is involved in growth, differentiation, and apoptosis of the cell. This signalling network is implicated in the development of most human cancers and hence is a prime target of anti-cancer molecular therapeutic agents (see Multi-million funded experiments could lead to revolution in cancer treatment (link opens in a new window)).

The EGFR teramer flat on the membrane
The EGFR teramer flat on the membrane

We use modelling and MD simulations to build and investigate models to explain FRET measurements taken by Marisa Martin-Fernandez' collaborating group.

The glutamine binding protein (GlnBP) is involved in the first stage of transporting glutamine (nutrient uptake) across the inner membrane of E. coli. GlnBP is the periplasmic - though not covalently bound - component of the corresponding ABC (ATP binding cassette) transport system. Upon ligand binding the 2-domain protein connected by a common hinge region undergoes an extreme conformational change. We are interested in the collective motions of GlnBP that are linked to its biological function. We also want to elucidate the closing mechanism of this protein. This project has been carried out in collaboration with Prof. Akio Kitao, Laboratory of Molecular Design (link opens in a new window), the University of Tokyo.

How does GlnBP close?
How does GlnBP close?

Coarse-Grained MD simulations

Whereas atomistic simulations can today reasonably be done for several hundred thousands to a few million atoms on the time scale of tens to hundreds of nano seconds, larger systems on a longer time scale are obviously still out of reach. To address this problem we apply CG simulations complementary to atomistic simulations. At the moment we are looking into the recent MARTINI force field (link opens in a new window) for lipids and proteins and assessing its value for membrane-receptor systems.

Using ab initio models in experimental structure determination

Molecular Replacement (MR) is one of the key methods available for determining protein structure from X-ray diffraction data. The method uses a trial structure to provide initial estimates of the phases.

Historically, ab initio models have been too inaccurate to give suitable phase estimates, and the method uses instead experimentally determined structures if these are available. The past few years have seen the progressive maturation of ab initio modelling, and we have been investigating the use of such models in MR to see if they are now reaching the required accuracy. While their use is clearly limited to certain sizes and classes of proteins, we have achieved some successes. (Read more ...)

Supporting Material

We provide coarse-grained coordinate sets for various membrane bilayer arrangements. (more info)


We have extended the functionality of the ptraj utility (AMBER9/AmberTools 1.x) to include a few handy routines like computation of mean residence times and our own diffusion code. (more info)

We have a few Tcl jiffies to help analyse the geometries of proteins and lipids, for use with VMD. (more info)

We have prepared a CHARMM script to do MM-PBSA calculations and also provide results from a sample simulation to play with. (more info)

Recent publication highlights

  1. J. Bibby, R. M. Keegan, O. Mayans, M. D. Winn and D. J. Rigden, Acta. Cryst.D68, 1622-1631 (2012)
    - "AMPLE: a cluster-and-truncate approach to solve the crystal structures of small proteins using rapidly computed ab initio models" (link opens in a new window)
  2. SK Roberts, CJ Tynan, M Winn, and ML Martin-Fernandez, Biochem. Soc. Trans.40, 189-194 (2012)
    - "Investigating extracellular in situ EGFR structure and conformational changes using FRET microscopy" (link opens in a new window)
  3. CJ Tynan, SK Roberts, DJ Rolfe, DT Clarke, HH Loeffler, J Kastner, MD Winn, PJ Parker and ML Martin-Fernandez, Mol. Cell. Biol., 31 2241-2252 (2011)
    - "Human Epidermal Growth Factor Receptor (EGFR) Aligned on the Plasma Membrane Adopts Key Features of Drosophila EGFR Asymmetry" (link opens in a new window)
  4. J. Kaestner and P. Sherwood, Mol. Phys., 108 293-306 (2010)
    - "The ribosome catalyzes peptide bond formation by providing high ionic strength"
  5. Hannes H. Loeffler and Martyn D. Winn, DL Technical Reports, DL-TR-2009-002 (2009)
    - "Large Biomolecular Simulation on HPC Platforms I. Experiences with AMBER, Gromacs and NAMD" (link opens in a new window)
  6. Hannes H. Loeffler and Akio Kitao, Biophys. J., 97 2541-2549 (2009)
    - "Collective Dynamics of Periplasmic Glutamine Binding Protein upon Domain Closure" (Featured Article) (link opens in a new window)
  7. Johannes Kaestner, Hannes H. Loeffler, Selene K. Roberts, Marisa L. Martin-Fernandez and Martyn D. Winn J. Struct. Biol., 167 117-128 (2009)
    - "Ectodomain orientation, conformational plasticity and oligomerization of ErbB1 receptors investigated by molecular dynamics" (link opens in a new window)
  8. D.J Rigden, R.M Keegan and M.D Winn, Acta Cryst.D64 1288-1291 (2008)
    - "Molecular Replacement using ab initio polyalanine models generated with ROSETTA" (link opens in a new window)
  9. Johannes Kaestner and Paul Sherwood, J. Chem. Phys.128, 014106 (2008)
    - "Superlinearly converging dimer method for transition state search" (link opens in a new window)
  10. Stephen E.D. Webb, Selene K. Roberts, Sarah R. Needham, Christopher J. Tynan, Daniel J. Rolfe, Martyn D. Winn, David T. Clarke, Roger Barraclough, and Marisa L. Martin-Fernandez, Biophys. J.94, 803-819 (2008)
    - "Single molecule imaging and FLIM show different structures for high and low-affinity EGFRs in A431 cells" (link opens in a new window)
  11. R.M.Keegan and M.D.Winn, Acta Cryst. D63, 447-457 (2007)
    - "Automated search-model discovery and preparation for structure solution by molecular replacement" (link opens in a new window)
  12. J Kaestner, S Thiel, HM Senn, P Sherwood, W Thiel, J. Chem. Theory Comput.3, 1064-1072 (2007)
    - "Exploiting QM/MM Capabilities in Geometry Optimization: A Microiterative Approach Using Electrostatic Embedding" (link opens in a new window)

Current vacancies