ENHANCED MEAN-FIELD SIMULATIONS OF ANTIBODY CDR LOOPS

蛋白质和核酸等重要生物分子精确的三维结构的获得，对于理解它们的功能以及合理设计药物化合物都有很大的帮助。然而，结构数据库相对较小。结构通常使用比较建模来构建。但是这些在环路区域中通常不太精确。将开发一种新的方法来预测蛋白质中高度准确的环构象，具体应用于抗体CDR环。这种平均场方法将大大增加交替构象的采样，同时保持与最先进的模拟技术，如分子动力学显式溶剂化的兼容性。单个水分子通常具有结构作用，并且用连续体模型替换可能导致不可接受的准确性损失。这是该方法相对于目前使用的方法的一个关键优势。由于该方法是基于能量的，因此比使用数据库的方法更通用，并且将改进结构建模的许多领域。该项目将包括制定一个强化的地方强化抽样办法。这将被应用于连续更困难的问题，在预测抗体环。最初的研究将集中在再现已知的情况下，诱导适合的重要H3环，其次是真正的预测系统中的H3构象是未知的。这些将提供新的见解的决定因素诱导适合，溶剂的作用和关键的结构细节的几个抗体的生物医学的重要性。随后的研究将预测几种催化抗体的抗体CDR区中的所有6个环。这些结构将有助于理解影响这些抗体的催化活性的因素，以及效率如何受到环柔性、溶剂分子或抗体所针对的过渡态类似物的缺陷的影响。该方法不仅可用于预测抗体的构象，还可用于预测抗体-抗原复合物的结构。这些信息对于理解这些重要的生物分子相互作用至关重要。

The availability of accurate three-dimensional structtires for important biomolecules such as proteins and nucleic acids can greatly aid in the understanding of their fimction, as well as in the rational design of pharmaceutical compounds. However, the structural database is relatively smaii. Structures are often built using comparative modeling. but these are typically less accurate in loop regions. A new approach to predict highly accurate loop conformations in proteins will be developed, with specific application to antibody CDR loops. This mean-field method will dramatically increase sampling of alternate conformations while maintaining compatibility with state of the art simulation techniques such as molecular dynamics in explicit solvation. Individual water molecules often have structural roles, and replacement with a continuum model may result in an unacceptable loss of accuracy. This is a key advantage of the method over those currently in use. Since the method is enezgy-based it is more general than those using databases, and will improve many areas of structural modeling. The project will consist of development of an enhanced locally Enhanced Sampling approach. This will be applied to successively more difficult problems in prediction of antibody loops. Initial studies will focus on reproducing known cases of induced fit for the important H3 loop, followed by true prediction for systems in which the H3 conformation is unknown. These will provide new insights into the determinants of induced fit, the role of solvent and key structural details for several antibodies of biomedical importance. Subsequent studies will predict all 6 loops in antibody CDR regions for several catalytic antibodies. These structures will aid in understanding the factors that influence the catalytic activity of these antibodies, and how efficiency is aifected by loop flexibility, solvent molecules or deficiencies in transition state analogs against which the antibodies are raised. The method will be extended to the prediction not only of antibody conformations, but also the structures of antibody-antigen complexes. This information can be critical to the understanding of these important biomolecular interactions.