Protein structure refinement through effective sampling and scoring

描述（由申请人提供）：通过有效的采样和评分来细化蛋白质结构。详细的结构信息对于详细了解生物过程和允许合理开发针对各种疾病的治疗策略至关重要。实验方法可以精确地确定高分辨率结构，但受到重大努力和实验限制的阻碍。作为一种替代方法，计算方法可以在一定程度上准确地预测蛋白质结构。然而，常规预测接近实验精度的蛋白质结构仍然是一个挑战。通过对初始模型的细化，可以达到较高的分辨率。成功的蛋白质结构优化需要能够产生原生构象的采样方法和能够在不了解真实实验结构的情况下从一组候选结构中识别最原生结构的评分方法。为了实现这些目标，开发了新的蛋白质结构预测和改进方案。特别介绍了基于现有和新的约束方法的有效构象采样策略，以减少构象搜索空间；开发了新的统计方法，以增强和结合现有的评分函数，从一组诱饵中选择精细模型；为了在能量精度、模型分辨率和采样效率之间取得更好的平衡，开发了中间分辨率模型PRIMO。这些新方法结合成一个集成的改进策略，并在自动化蛋白质结构管道的背景下应用。

DESCRIPTION (provided by applicant): Protein structure refinement through effective sampling and scoring. Detailed structural information is essential in understanding biological processes in detail and in allowing the rational development of therapeutic strategies against a variety of diseases. Experimental methods allow the accurate determination of high-resolution structures, but are encumbered by significant effort and experimental constraints. As an alternative, computational methods can predict protein structures to some degree of accuracy. However, it has remained a challenge to routinely predict protein structures at near-experimental accuracy. A high level of resolution may be reached through refinement of initial models. Successful protein structure refinement requires sampling methods that can generate native-like conformations and scoring methods that are able to identify the most native structures from a set of candidates without any knowledge of the true experimental structure. In order to achieve these goals novel protein structure prediction and refinement protocols are developed. In particular, effective conformational sampling strategies based on existing and new methods with constraints to reduce conformational search space are introduced; novel statistical methods to enhance and combine existing scoring functions in the selection of refined models from a set of decoys are developed; and an intermediate resolution model PRIMO is developed to obtain a better balance between energetic accuracy, model resolution, and sampling efficiency. These new methods are combined into an integrated refinement strategy and applied in the context of an automated protein structure pipeline.