Neutron Diffraction and MD Studies of the Studies of the Structure of Aqueous Sol

描述(申请人提供)：这项拟议的项目将是对复杂生物分子溶质水溶液结构正在进行的研究的继续，使用分子动力学模拟和中子衍射与同位素替代(NDIS)实验相结合的方法。尽管中子衍射是研究液体结构最有用的实验方法，但生物分子溶液的总散射的复杂性使得这种实验很难从特定的结构细节来解释。开发NDIS方法是为了帮助简化对这种散射的解释，但对于糖等大型不对称溶质，由于每个被取代的氢原子处于不同的环境中，因此仍然不能从具体细节的角度来解释散射。本项目克服了这一问题，只在一个位置使用专门取代的糖溶液，使NDIS实验能够探测单个原子周围的原子结构。然后，可以将这些仍然复杂的特定结构因素直接与MD模拟计算的结构因子进行比较，作为确定模拟准确性的一种手段，如果表示良好，则可以使用模拟提供的丰富信息来详细解释实验数据。这种方法实际上开辟了水溶液中复杂分子结构分析的新领域。拟议的扩展将应用这些新开发的程序来进一步研究其他重要生物分子在水溶液中的结构。一种新的实验浓度依赖分析将允许分子间溶剂化结构与分子内结构分开提取。另外的分子内结构研究将用于分析溶质中的氢键和溶质的构象，以及它们如何受到溶剂化的影响。除了对具有生物重要性的单糖及其类似物进行系统分析外，这项技术还将扩展到氨基酸、核苷酸和其他小型生物溶质的研究。这项工作对公众健康很重要，因为水溶剂化在所有生物系统中的重要性，以及在确定生物分子功能方面的重要性。这些基本信息对于设计药物分子和生物配体以及了解疾病机制和正常生物系统的功能都是必不可少的。

DESCRIPTION (provided by applicant): This proposed project will be the continuation of an on-going study of the structure of aqueous solutions of complex biomolecular solutes using a combination of MD simulations and neutron diffraction with isotopic substitution (NDIS) experiments. Although neutron diffraction is the most useful experimental method for the study of liquid structure, the complexity of the total scattering from a biomolecular solution has rendered such experiments very difficult to interpret in terms of specific structural details. The NDIS method was developed to help simplify the interpretation of this scattering, but for large asymmetric solutes such as sugars, the scattering still cannot be interpreted in terms of specific details since each substituted hydrogen atom is in a different environment. The present project has overcome this problem by using sugar solutes specifically substituted at only a single position, allowing the NDIS experiment to probe the atomic structuring around just a single atom. These still complicated specific structure factors can then be compared directly to those calculated from MD simulations, as a means of determining the accuracy of the simulations, and if the representation is good, the wealth of information available from the simulations can be used to interpret the experimental data in detail. This method has in effect opened a new field of structural analysis of complex molecules in aqueous solution. The proposed extension will apply these newly-developed procedures to further studies of structuring in aqueous solutions of additional important biological molecules. A new, experimental concentration-dependent analysis will allow the intermolecular solvation structure to be extracted separately from the intramolecular structure. Additional intramolecular structuring studies will be used to analyze hydrogen-bonding in solutes and the conformations of solutes and how they are affected by solvation. In addition to a systematic analysis of the biologically-important simple monosaccharides and their analogs, the technique will be extended to studies of amino acids, nucleotides, and other small biological solutes. This work is important for public health because of the importance of aqueous solvation in all biological systems, and in determining the functioning of biomolecules. Such basic information is essential in designing drug molecules and biological ligands and in understanding both disease mechanisms and the functioning of normal biological systems.