Transition Pathways for Biomolecular Systems: Theory and Computation

描述(由申请人提供)：对分子构象转变的描述是科学和技术的基础。了解这些途径不仅提供了中间体的知识，而且对设计用于技术或制药目的的蛋白质配体以及设计分子机器也很有用。在发生构象变化的情况下，计算结合亲和力时通常也需要这种知识。通过实验获得这种信息是困难和/或昂贵的，这促使了计算机模拟的广泛使用。然而，目前寻找大分子体系的过渡路径或结合自由能的方法是有限的。对于小分子的有希望的结果表明，这种方法是可以开发的，这是本项目的目标。将构建稳健和高效的方法来计算过渡路径，并将其应用于生物学上感兴趣的系统，如SRC蛋白酪氨酸激酶。将开发创新技术，以获得合理的一次近似，并对其进行改进。这些路径将被定义为对于精心选择的一组约化变量的某些泛函的最小值。此外，在计算结合自由能时，通常需要路径。这里开发的技术将与最近发表的使用限制势的自由能方法相结合。通过采用先进的采样方法，该方法将应用于更大的系统，如参与DNA转录的KID：KIX和cMyb：KIX复合体。将通过与软件开发人员以及新的独立软件的既定联系来传播这一方法。了解蛋白质的活性及其与药物的相互作用是开发疾病治疗方法所必需的。计算机能力的不断增强使得在实验室进行实验之前在计算机上进行研究变得具有成本效益。然而，这也需要使用高级数学的复杂软件的可用性，其开发是本项目的目标。

DESCRIPTION (provided by applicant): A description of conformational transitions in molecules is fundamental to science and technology. Knowing the pathways not only provides knowledge of the intermediates but is useful in designing protein ligands for technological or pharmaceutical purposes and in designing molecular machines. This knowledge is also often needed for calculating binding affinities in cases where conformational changes occur. Obtaining this information experimentally is difficult and/or costly, which motivates the wide use of computer simulations. However, the current methods for finding transitional paths or binding free energies for large molecular systems are limited. Promising results for smaller molecules suggest that such methods can be developed, which is the objective of this project. Robust and efficient methods will be constructed for the calculation of transitional paths and their application to biologically interesting systems such as SRC protein tyrosine kinase. Innovative techniques will be developed for obtaining reasonable first approximations and for refining them. These paths will be defined as the minimum of some functional for a well chosen set of reduced variables. In addition, pathways are often needed for the calculation of free energies of binding. The techniques developed here will be combined with a recently published free energy method that uses a restraining potential. By employing advanced sampling methods, the method will be applied to larger systems such as KID:KIX and cMyb:KIX complexes involved in DNA transcription. The methodology will be disseminated through established contacts with software developers as well as new stand-alone software. Understanding the activity of proteins and their interactions with drugs is needed for developing treatments for disease. The increasing power of computers makes it cost effective to do studies on the computer prior to experiments in the laboratory. However, this also requires the availability of sophisticated software employing advanced mathematics, whose development is the aim of this project.