Probing the Structure/Function/Dynamics Relationship in Biomolecular Complexes with Multiscale Computational Techniques

项目摘要： 在过去的二十年里，由于同步辐射技术的进步，分子生物学 方法和计算资源，在确定 生物分子的构象，导致了深刻的结构和功能的见解。但还有另一 生物功能的一个重要方面，即动力学，这是，迄今为止，探索不足。这创造了一个 严重的盲点阻碍了全面了解大分子功能的进展， 生物过程。这项建议的主要目标是利用和发展计算机模拟 通过对生物分子动力学进行严格建模， 了解生物过程。更具体地说，我们将开展三个相互关联的项目。第一、 我们将确定染色质重塑因子如何影响核小体的动力学， 染色质纤维作为表观遗传基因调控的手段。其次，我们将研究关键的机制， 细菌中的毒力因子，包括它们如何从宿主中缺乏铁，以及它们如何防御 自己从肽模拟物。最后，我们将开发计算方法， 模拟不同生物分子复合物的溶液小角X射线散射实验结果。 这些研究的完成将揭示结构之间关系的复杂细节， 功能和动力学的多组分生物分子复合物在一个广阔的时间和长度范围 鳞片此外，科学目标之间的协同作用，以及计算方法和 在每个项目中进行强有力的实验合作，将促进新的机会和领域， MIRA奖将允许我们进行的科学研究。总的来说，这项工作将解决一系列 关键生物过程知识的根本差距，并将为未来的生物学研究奠定基础。 这些研究将改善人类疾病的治疗和预防。

Project Summary: Over the last two decades, enabled by progress in synchrotron radiation techniques, molecular biology methods, and computational resources, there has been tremendous progress in determining the conformations of biomolecules that has led to deep structural and functional insights. But there is another dimension to biological function, namely dynamics, which is, as yet, underexplored. This has created a serious blind spot that inhibits progress towards a full understanding of macromolecular functions and biological processes. The broad objective of this proposal is to utilize and develop computer simulations that address this deficiency in knowledge by rigorously modeling biomolecular dynamics to increase our understanding of biological processes. More specifically, we will pursue three interrelated projects. First, we will determine how chromatin remodeling factors influence the dynamics of nucleosomes and chromatin fibers as a means of epigenetic gene regulation. Second, we will examine the mechanisms of key virulence factors in bacteria, including how they scagence iron from hosts and how they defended themselves from peptidomimetics. Finally, we will develop computational methods that more effectively model the results of solution small angle X-ray scattering experiments for diverse biomolecular complexes. Completion of these studies will reveal intricate details about the relationship between the structure, function, and dynamics of multicomponent biomolecular complexes across a vast range of time and length scales. Furthermore, the synergy between the scientific goals, as well as the computational methods and strong experimental collaborations in each of these projects, will foster new opportunities and areas of scientific inquiry that the MIRA award will allow us to pursue. Overall, this work will address a series of fundamental gaps in knowledge for critical biological processes, and will lay the foundation for future studies that will improve the treatment and prevention of human ailments.