Figure 1: 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.
Figure 2: 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 sample quality control, experimentation, data interpretation and model validation in structural biology, with a major focus on macro-molecular crystallography.
To fully understand the function of biological systems, accurate structural models of their components (small-molecule ligands, DNA, RNA, proteins and macromolecular assemblies) are required. Therefore, the focus of the group’s activities is the development of the required methodologies, their application to projects of biomedical interest and their implementation in ARP/wARP – scientific software project with over 6,000 citations. Given the exciting opportunities for structural biology arising with the availability of the European X-ray Free Electron Laser (FEL) from 2017, our portfolio is complemented by relevant research and development.
Previous and current research
Targets of biomedical interest
We integrate X-ray crystallography, lower resolution imaging, biochemistry, computational biology and biophysical methods to investigate targets of biomedical interest. These include: characterisation of components of the telomerase complex relevant to conditions with age disorder and cancer (Zvereva et al., 2013), inhibitor development to combat bacterial antibiotic resistance (Grigorenko et al., 2017) and structural studies of cyanobacterial cells and their proteins involved in toxicity.
Computer-aided drug design
We make use of sophisticated algorithms to develop new tools for drug discovery (Carolan et al., 2014). Our ViCi software enables in silico screening of known ligands to provide new leads for drug design.
Biological imaging with FELs
Through international collaboration we are developing novel computational tools for the interpretation and modelling of measured diffraction data. By focusing on the imaging of cellular nuclei, we explore the potential for single particle imaging experiments (Giewekemeyer et al., 2015).
Methods for biological structure determination
We develop a comprehensive range of algorithms for protein/ligand/DNA/RNA X-ray crystal structure determination and validation. We exploit the inherent properties of macromolecular structures and integrate additional information derived from a priori knowledge and dedicated databases.
Our main methodological focus is the ARP/wARP software project for macromolecular crystallography. For the automated interpretation of X-ray and high-resolution electron microscopy density maps we make use of image and pattern recognition techniques, statistical analysis, data mining and bioinformatics tools. To provide users with easy access to quality assessment and model completion we have developed a user-friendly molecular viewer – ArpNavigator (Langer et al., 2013).
Future projects and goals
Together with international collaborators, we will undertake novel pilot projects aiming at the interpretation of structural data obtained from various sources and projects of biomedical or biotechnological importance. Driven by general academic interest, we will continue to focus on methods development for structural biology, addressing challenging studies of large macromolecular complexes. We will also continue contributing to the provision of computational services, synchrotron beamline facilities and applications for FEL-based diffraction.