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 and data interpretation in structural biology, with a major focus in macromolecular 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 (Langer et al., 2008) – a world-leading software project. Given the breathtaking opportunities for structural biology arising with the availability of the European X-ray Free Electron Laser (FEL) from 2017, relevant research and development complement the group’s portfolio.
Previous and current research
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: structural characterisation of components of the telomerase complex (Zvereva et al., 2013) relevant to conditions with age disorder and cancer, inhibitor development for beta-lactamase (Grigorenko et al., 2013) to combat antibiotic resistance, and studies of the nuclear pore complex. We also investigate the pathway of amyloid fibril formation via fragments of human gelsolin and class I hydrophobins (Kallio et al., 2011).
Computer-aided drug design
We make use of various novel algorithms and, through their combination (Carolan et al., 2014), develop new tools for drug discovery. Our ViCi software enables 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 FELs
We are developing protocols for the preparation and handling of biological samples and novel computational tools for the interpretation of measured diffraction data (Mancuso et al., 2012). Focusing on the imaging of cellular nuclei, we explore the potential for single particle imaging experiments (Giewekemeyer et al., 2015). In collaboration with the DESY Detector group and the P11 beamline staff, we probe the properties of the novel AGIPD detector, which will be used at the European XFEL.
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. 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 electron density maps we make use of sophisticated 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 medical or biotechnological importance. Driven by general academic interest, we will continue to focus on methods development for structural biology, addressing the challenges of limited resolution of the data and large size of macromolecular complexes. We will also continue contributing to the provision of computational services, synchrotron beamline facilities and applications for FEL-based diffraction.