CCP4 Advanced integrated approaches to macromolecular structure determination

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The generic importance of macromolecular crystallography in general and CCP4 in particular is provided in the Pathways to Impacts section.

CCP4 users in the pharmaceutical and biotechnology sector are most often involved in the study of protein-ligand (most often drug) complexes. The critical computational step in this process is molecular replacement (MR), in which a known atomic model from a similar structure is used to explain the diffraction pattern of the unknown structure. The MR approach is used in more than 70% of structure solutions. However it is not uncommon for the molecular replacement to yield a poor electron density map due to changes in the conformation of the protein. The software developed in this work package aims to significantly reduce the number of cases in which problems occur by increasing the range of convergence of the initial refinement of the MR model, while dramatically increasing the speed of the refinement step to allow screening many more candidate models.

Cryo-Electron Microscopy (EM) is an increasingly important method for the determination of the structure of pathogens and complexes. The same methods will also be implemented for cryo-EM data, where the resolution tolerance of the methods will facilitate the interpretation of lower resolution reconstructions.

Improvement of the protein model also improves the electron density for the unmodelled ligand or drug, since the electron density features of the known and unknown regions of the structure are related through the diffraction pattern. The speed and radius of convergence of the new method will increase the coverage of automated methods for high throughput screening, which are widely used in the commercial sector. The impact of these developments will be to reduce the number of cases where structure solutions fails, to reduce the level of manual intervention required in successful studies, and to increase the accuracy of the resulting structures.

YSBL has played a significant role in the commercial impact of CCP4: two YSBL-originated developments (the REFMAC and COOT software) have been the most-used tools in their field. Several other YSBL developments (DM, MOLREP, BUCCANEER, CCP4I) have citation counts in the hundreds to thousands are are significantly used in industry. The YSBL group engage with commercial customers through through commercial representation on the CCP4 Executive Committee and Working Groups 1 and 2, through workshops and the CCP4 bulletin board. CCP4 developers including the York group. The working groups provide guidance on which strategic planning is built.

The software produced will be added to the CCP4 suite, and where appropriate to the related CCP-EM software suite for electron microscopy. The CCP4 suite is in use world-wide and is available on Windows, Linux and Mac_OS platforms, providing a direct distribution channel to the overwhelming majority of macromolecular crystallographers. Libraries and methods will be available to other packages as well. CCP4 is updated with major version releases roughly every year, and automated updates on a roughly monthly basis to enable fast access to new developments. As a result, once the software has been added to the package it will within months be available to both the academic and commercial user community.