Computation for Structural Biology: Tools to Enable Dynamic 3-D Reconstruction of Time-varying Viral Structures

普渡大学研究基金会doerschuk， Peter CA计算结构生物学的关键挑战是确定病毒的三维结构，特别是三维结构的动态变化，这对理解病毒的功能至关重要。这一信息对于合理设计对抗病毒感染的药物以及将病毒用于其他目的（例如，作为靶向向特定器官输送药物的载体）至关重要。解决这些问题涉及到两个数值计算问题的新算法的开发、分析、实现和使用，即全局优化和多维正交。研究人员通过定位成本的全局最小值来计算三维结构，该成本是实验数据和预测器的函数，并量化了数据与数据预测之间的差异。预测器的评估需要进行多维正交，它是描述病毒三维结构和数据收集过程中任何未知方面的参数的函数，并且是对这些参数的最小化。该方法的性能受到全局优化和正交工具的限制，因此这些工具是本研究的重点。关键的全局优化问题是利用数据的多尺度结构和参数的成本，由于傅里叶变换的存在，以及在评估成本的准确性和计算费用之间的权衡，由于嵌入正交。关键的多维正交问题是不寻常的积分和积分区域，例如，在定义三维旋转的三个欧拉角上对具有二十面体对称性的三个变量函数进行积分。

Proposal #0098156Purdue Research FoundationDoerschuk, Peter CA key challenge in computational structural biology is the determination of the 3-D structure of a virus, andespecially dynamical changes in 3-D structure which are central to understanding the function of the virus. This information is central to rational design of drugs to combat viral infections and to the use of viruses for other purposes, e.g., as vehicles for the targeted delivery of drugs to specific organs. Solving these problems involves the development, analysis, implementation and use of new algorithms for two numerical computation problems, global optimization and multidimensional quadrature.The investigators compute a 3-D structure by locating the global minimum of a cost which is a function of experimental data and of a predictor, and which quantitates the difference between the data and the prediction of the data. The predictor, whose evaluation requires multidimensional quadrature, is a function of parameters describing the 3-D structure of the virus and any unknown aspects of the data collection process and the minimization is with respect to these parameters. Performance of the approach is limited bythe global optimization and quadrature tools and therefore these tools are the foci of this research. Key globaloptimization issues are exploiting the multi-scale structure of the data and parameters in the cost due to the presence of Fourier transforms and the tradeoff between accuracy and computational expense in the evaluation of the cost due to embedded quadratures. Key multidimensional quadrature issues are the unusual integrands and regions of integration, e.g., to integrate a function of three variables with icosahedral symmetry over the three Euler angles that define a 3-D rotation.