Integrative modelling for structural biology
A selection of model-viewing options in ArpNavigator. Shown clockwise from the top left are a stick representation in solid electron density, a ball-and-stick representation in planar density, a skeleton representation of the electron density shown as a mesh and the protein in cartoon representation in planar density.
A known inhibitor in green, aligned with two hits from the ViCi software, in the binding pocket of beta lactamase. Important interactions maintained are highlighted with red circles and those created for exploration with full red spots
The Lamzin group applies and develops cutting-edge computational methods and experimental approaches for structural studies of molecules of biological and medical interest.
To fully understand the function of biological systems, accurate structures of their components – DNA, RNA, proteins, macromolecular complexes and assemblies – are required. We apply and develop cutting-edge computational methods and experimental approaches for sample quality control, experimentation and data interpretation in macromolecular crystallography and with the use of X-ray free-electron lasers that may also have potential use in electron microscopy.
Previous and current research
Methods for biological structure determination: We develop a comprehensive range of algorithms for protein/ligand/DNA/RNA X-ray crystal structure determination and new procedures for dealing with challenging problems (Hattne and Lamzin, 2011). We exploit inherent properties of macromolecular structures (Wiegels and Lamzin, 2012) and integrate additional information derived from a priori knowledge and dedicated databases. The group’s main methodological focus is the ARP/wARP software project (Langer et al., 2008) for macromolecular crystallography, which is based on the use of pattern-recognition methods. An intuitive and user-friendly molecular viewer – the ArpNavigator (Langer et al., 2013) – enables user control of the model building process and provides easy access to a range of methods for quality assessment and model completion.
Structure-based drug design: We make use of various novel algorithms and, through their combination (Langer et al., 2012), develop new tools for drug discovery. The ViCi software allows for the in silico screening of known ligands to provide new leads for drug design. Our interest in this direction is stimulated by our research into the biology of pathogenic species associated with human morbidity and mortality, and is focused on the probing of bacterial antibiotic resistance.
Biological imaging with Free-Electron Lasers (FEL): Breathtaking results from initial diffractive imaging experiments using coherent FEL radiation (Siebert et al., 2011) show the potential for imaging cellular organelles and understanding dynamics of complex formation. In order to exploit the numerous novel and unique opportunities for structural biology that will be provided by the European X-ray FEL source near DESY (www.xfel.eu), we are developing protocols for handling of biological samples for FEL experiments as well as novel computational methods for the interpretation of measured data (Mancusi et al., 2012). We succeeded in 3D imaging of frozen-hydrated S. cerevisiae cells using ptychographic coherent X-ray diffractive imaging.
Other targets of biomedical interest: We integrate X-ray crystallography, lower resolution imaging, biochemistry, computational biology and biophysical methods in order to investigate targets of biomedical interest. These include the nuclear pore complex and hydrophobins (Kallio and Rouvinen, 2011), which may be used in drug delivery to solubilise hydrophobic pharmaceuticals. We also investigate the pathway of amyloid fibril formation via class I hydrophobins and fragments of human gelsolin.
Future projects and goals
The group will continue to focus on crystallographic software development driven by general academic interest, provision of state-of-the-art beamline facilities at PETRA III in Hamburg, future applications of such developments to FEL-based diffraction, and by the potential use of such developments in projects of medical or biotechnological importance. Together with our international collaborators, we will undertake novel pilot projects aiming at interpretation of structural data obtained from various sources.