Theoretical Studies of Protein Folding

描述（由申请人提供）：本研究项目的长期目标是开发高分辨率蛋白质结构的可靠和准确预测方法，从氨基酸序列开始，以及蛋白质活性位点的低能量替代构象的枚举。实现这些目标将使基于结构的药物设计方法能够通过同源性建模有效地应用于比目前可行的更广泛的靶标；这也将使药学上有趣的配体被设计成符合计算所阐明的不同构象。为了实现这些目标，必须开发改进的分子力学力场、水溶液溶剂化模型以及能够以速度和可接受的精度搜索相空间的采样算法。在这些领域提出了新的努力，以及开发一个集成的蛋白质建模包，这将使该技术能够被生物医学界的其他人使用。将对各种模型和计算方法进行广泛的基准测试，以对照实验数据，在某些情况下将与其他主要研究人员合作。该方法的特定生物学应用将涉及对药物靶点（如激酶）的同源性建模。

DESCRIPTION (provided by applicant): The long term goal of this research program is the development of methods for robust and accurate prediction of protein structures to high resolution, starting from the amino acid sequence, as well as enumeration of low energy alternative conformations of protein active sites. Achievement of these objectives would enable structure based drug design methods to be effectively applied to a much wider range of targets, via homology modeling, than is currently feasible; it would also enable pharmaceutically interesting ligands to be designed to fit into the alternative conformations elucidated by the computations. To accomplish these goals, it is essential to develop improved molecular mechanics force fields, models for aqueous solvation, and sampling algorithms capable of searching phase space with both speed and acceptable accuracy. Novel efforts in each of these areas are proposed, as well as the development of an integrated protein modeling package which will enable the technology to be used by others in the biomedical community. Extensive benchmarking of various models and computational methods against experimental data will be performed, in some cases in collaboration with other leading researchers. Specific biological applications of the methods will involve homology modeling of pharmaceutically interesting targets, such as kinases.