Lamzin Group

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.

Lamzin Group

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 macromolecular crystallography.

To fully understand the function of biological systems, accurate structures of their components – DNA, RNA, proteins and macromolecular assemblies – are required. Given the breath-taking opportunities for structural biology arising with the availability of the European X-ray Free Electron Laser (FEL) from 2017, relevant research and development are becoming a focus of the group’s activities.

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 fi bril formation via class I hydrophobins (Kallio et al., 2011) and fragments of human gelsolin, which may be used in drug delivery to solubilise hydrophobic pharmaceuticals.

Structure-based 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 preparation and handling of biological samples and novel computational methods for the interpretation of measured FEL data (Mancuso et al., 2012). Our focus is on the imaging of cellular organelles like nuclei or mitochondria, exploiting the potential for single particle imaging experiments of FELs.

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 inherent properties of macromolecular structures (Grigorenko et al., 2013) 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, 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.

Future projects and goals

Together with international collaborators, we will undertake novel pilot projects aiming at interpretation of structural data obtained from various sources and projects of medical or biotechnological importance. We will continue to focus on software development for structural biology driven by general academic interest and continue contributing to provision of computational services, beamline facilities and applications for FEL-based diffraction.

Chemistry at EMBL