Universiteit Leiden

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Research project

Developing computational algorithms for structural biology

A high resolution, three dimensional view of a molecule provides detailed information that help elucidate its function: by knowing the exact arrangement of atoms in a molecule, we can understand disease, develop drugs to combat them and improve technology.


Experimental methods, such as X-ray crystallography and electron microscopy, require computational methods to obtain an accurate three dimensional representation. The structure solution process is difficult and fails in cases when only data with a weak signal can be obtained. In particular, weak data from large macromolecular complexes and membrane proteins of considerable medical interest do not allow structure solution. The main research interest of Dr. Pannu is to develop novel algorithms to solve structures from data with a weak signal.

Currently, structure determination relies on a multi-step approach with successive approximations of the experimental data in each step. Raj Pannu wishes to develop methods that combine all the experimental data with all the relevant prior information in one step.

Novel algorithms allow structure solution when current methods fail.  For example, the application of the above algorithm to low resolution X-ray diffraction data from RNA polymerase II crystals has led to an automatically built molecule when current methods fail. The Figure shows the electron density of a portion of a molecule shown in blue and the automatically built model is multicoloured.

The end goal of the research is to meet the urgent need to solve macromolecular structures from data with a weak signal in software that seemlessly automates the process and is ideal for non-specialists.

Key publications

  1. Kuzmanic, A., N.S. Pannu, B. Zagrovic, "X-ray refinement significantly underestimates the level of microscopic heterogeneity in biomolecular crystals", Nature Communications, vol. 5, Feb, 2014. DOI: 10.1038/Ncomms4220
  2. Skubak, P., N.S. Pannu, "Automatic protein structure solution from weak X-ray data", Nature Communications, vol. 4, Nov, 2013. DOI: 10.1038/Ncomms3777
  3. Murshudov, G.N., P. Skubak, A.A. Lebedev, N.S. Pannu, R.A. Steiner, R.A. Nicholls, M.D. Winn, F. Long, et al., "REFMAC5 for the refinement of macromolecular crystal structures", Acta Crystallographica Section D-Biological Crystallography, vol. 67, pp. 355-367, Apr, 2011. DOI: 10.1107/S0907444911001314
  4. Ness, S.R., R.A.G. de Graaff, J.P. Abrahams, N.S. Pannu, "CRANK: New methods for automated macromolecular crystal structure solution", Structure, vol. 12, no. 10, pp. 1753-1761, Oct, 2004. DOI: 10.1016/J.Str.2004.07.018
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