Transition Pathways for Biomolecular Systems: Theory and Computation

描述（由申请人提供）：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，而且有助于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。 在发生构象变化的情况下，计算结合亲和力通常也需要这些知识。 通过实验获得这些信息是困难的和/或昂贵的，这促进了计算机模拟的广泛使用。 然而，目前寻找大分子系统的过渡路径或结合自由能的方法是有限的。 对于较小分子的有希望的结果表明可以开发这样的方法，这是该项目的目标。 将构建稳健且有效的方法来计算过渡路径及其在生物学上有趣的系统（例如 SRC 蛋白酪氨酸激酶）中的应用。 将开发创新技术以获得合理的第一近似值并对其进行改进。 这些路径将被定义为精心选择的一组简化变量的某些函数的最小值。 此外，计算结合自由能通常需要路径。 这里开发的技术将与最近发布的使用约束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，例如参与 DNA 转录的 KID:KIX 和 cMyb:KIX 复合物。 该方法将通过与软件开发人员建立的联系以及新的独立软件进行传播。开发疾病治疗方法需要了解蛋白质的活性及其与药物的相互作用。计算机功能的不断增强使得在实验室实验之前在计算机上进行研​​究变得具有成本效益。 然而，这也需要使用先进数学的复杂软件的可用性，该软件的开发是该项目的目标。

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.