Invariom modelling for crystal structures of biological macromolecules: Rapid and accurate calculation of important molecular properties of selected antibiotic and protein molecules

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Protein crystallography at ultrahigh resolution is a new area of research that attracts considerable interest. Recent review articles [1, 2, 3] see high-resolution protein crystallography in a positive light and predict interesting future outcomes. Although this point of view can only be agreed upon, it is usually not pointed out that the number of structures that are currently amenable to an accurate evaluation via multipole refinement (< 20) is only a negligible fraction of the data sets currently in the PDB [4]. To solve this problem, current or expected advances in data collection procedures are emphasized. The methodologies of an accurate evaluation that takes into account fine details of the electron density distribution ρ(r) as well as of data collection of ultrahigh resolution structures are in their infancy.In this research project invariom modeling provides a way to considerably increase the fraction of protein structures (to ca. 400) that can accurately be analyzed, thereby leading to structural data of superior quality. This will simultaneously lead to the establishment of modeling with aspherical scattering factors as a standard method for refinement of organic small-molecule structures. Invariom modeling will routinely provide additional information for these structures, such as improved geometries and the electrostatic potential to name but a few. In addition, such electron-density derived properties will also be obtained for peptide- and glycopeptide antibiotics, in order to deepen insight into their biological function. By increasing quality and information content of X-ray structures it is foreseen that an important contribution to structure-based drug design [5, 6] will be made.The development of the invariom approach is not yet completed. With methodology currently available, the electron density distribution in the solid state (i.e. in the crystal) can not be calculated for systems with more than 50 atoms per molecule. Conventional charge density studies will be an integral part of this research project, as they allow to determine the electron density distribution in the crystal, as opposed to the isolated molecular density. The understanding of the differences between isolated molecular and crystal density, with the aim of modeling the effects of re-distribution together with invariom fragments, is another aim of the research scheme.