Automated Structure Determination of Protein-Ligand Complexes

Soaking and co-crystallization experiments for studying the binding of potential drugs with proteins of known structure are a significant research function of crystallographic labs in pharmaceutical companies. Such experiments have two overriding characteristics: (a) the experiments are repetitive, and therefore become routine, and (b) numerous experiments are performed to acquire the desired information and understanding.

Our goal is to develop a software system that reduces human intervention 10-fold in all stages of structure determination for experiments involving isomorphous crystals. An important part of this proposal is the determination of appropriate criteria to measure quality during the process and to reject cases not meeting specifications controlled by the scientist. In Phase I, we propose to build a prototype, referred to hereafter as X-LIGAND, to process a series of soaking experiments. The functionality in this prototype is a superset of what is required to study mutant proteins, and so would establish the feasibility of automating that process as well.