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

超高分辨率蛋白质晶体学是一个新的研究领域，引起了人们的极大兴趣。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，但通常没有指出，目前可以通过多极精化（< 20）进行准确评估的结构数量仅占目前PDB bbb中数据集的微不足道的一部分。为了解决这个问题，强调了数据收集程序当前或预期的进展。考虑到电子密度分布ρ(r)的精细细节以及超高分辨率结构的数据收集的准确评估方法尚处于起步阶段。在本研究项目中，不变模型提供了一种方法，可以大大增加可以准确分析的蛋白质结构的比例（约为400），从而产生高质量的结构数据。这将同时导致建立非球面散射因子模型，作为改进有机小分子结构的标准方法。不变性建模通常会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等等。此外，这种电子密度衍生的性质也将用于多肽和糖肽抗生素，以加深对其生物学功能的了解。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]。不变性方法的发展尚未完成。根据目前可用的方法，对于每个分子超过50个原子的系统，固态（即晶体）中的电子密度分布无法计算。传统的电荷密度研究将是本研究项目不可或缺的一部分，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。研究计划的另一个目标是了解分离分子和晶体密度之间的差异，以模拟再分布和不变片段的影响。

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.