X-ray crystallography is a critical tool in modern drug design. Ligand and/or fragment screening campaigns for drug design are typically carried out by collecting diffraction data at 100 K from large (> 30 mm), robust, well diffracting crystals. However, there is increasing evidence that crystal soaking protocols are more efficient when applied to smaller crystals and that the cryo-cooling of crystals may obscure biologically relevant information. Post ESRF-EBS X-ray beams will allow us to apply recently developed multi-crystal (MDX) data collection protocols to complexes of micro-crystals with small molecules. However, how best to combine the partial data sets obtained in MDX in order to obtain the best electron density for bound fragments or ligands and the best analysis of modes of binding to their target molecules is an area requiring optimisation.
The aims of this PhD work are:
1). To provide a systematic analysis of the effect of crystal size of the ligand/fragment occupancy obtained in soaking experiments;
2). To improve and optimize protocols for the combination of MDX data sets using enhanced protocols for hierarchical cluster analysis (HCA) and genetic algorithms (GAs), areas which are being actively developed at ESRF.
The project proposed here is based on a combination of methodology development at the ESRF and access to material, training expertise and insight from IDRS Servier, Suresnes, France. This opportunity will thus provide an unrivalled opportunity for a young scientist interested in optimising structure-based drug design processes, which exploit microcrystals. During the PhD work, the student will learn experimental methodology (protein production and purification, crystallisation, diffraction data collection, data analysis) and interpretation of real-world results in an area designed to overcome major bottlenecks in the drug design process.
Further information may be obtained from Max Nanao (tel.: +33 (0)4 76 88 4087, email: email@example.com).
Contract of two years renewable (subject to satisfactory progress) for one year.
The ESRF is an equal opportunity employer and encourages diversity.
The European Synchrotron, the ESRF, is an international research centre based in Grenoble, France.
Through its innovative engineering, pioneering scientific vision and a strong commitment from its 700 staff members, the ESRF is recognised as one of the top research facilities worldwide. Its particle accelerator produces intense X-ray beams that are used by thousands of scientists each year for experiments in diverse fields such as biology, medicine, environmental sciences, cultural heritage, materials science, and physics.
Supported by 22 countries, the ESRF is an equal opportunity employer and encourages diversity.