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

高分辨率蛋白质晶体学是一个新的研究领域，引起了人们极大的兴趣。最近的综述文章[1，2，3]从积极的角度看待高分辨率蛋白质晶体学，并预测了有趣的未来结果。虽然这一观点只能达成一致，但通常不会指出，目前通过多极细化（< 20）进行准确评估的结构数量仅占PDB [4]中当前数据集的一小部分。为解决这一问题，强调了数据收集程序方面目前或预期的进展。考虑到电子密度分布ρ（r）的精细细节的精确评估方法以及对高分辨率结构的数据收集还处于起步阶段。在本研究项目中，不变量建模提供了一种方法，可以大大增加蛋白质结构的分数（约为100%）。400)从而产生上级质量的结构数据。这将同时导致非球面散射因子建模的建立，作为一种标准的方法来细化有机小分子结构。不变量建模将常规地为这些结构提供额外的信息，例如改进的几何形状和静电势，仅举几例。此外，这种电子密度衍生的性质也将获得肽和糖肽抗生素，以加深对它们的生物学功能的了解。通过提高X射线结构的质量和信息含量，可以预见将对基于结构的药物设计做出重要贡献[5，6]。利用目前可用的方法，对于每个分子具有超过50个原子的系统，不能计算固态（即在晶体中）中的电子密度分布。传统的电荷密度研究将是该研究项目的一个组成部分，因为它们可以确定晶体中的电子密度分布，而不是孤立的分子密度。孤立的分子和晶体密度之间的差异的理解，与不变的片段一起建模的影响的目的，是研究计划的另一个目的。

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.