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

项目总结： 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 生物分子的构象带来了深刻的结构和功能洞察。但还有另一个 生物功能的维度，即动力学，到目前为止还没有得到充分的探索。这创建了一个 严重的盲点，阻碍了对大分子功能和 生物过程。这项提议的广泛目标是利用和开发计算机模拟 通过对生物分子动力学进行严格建模来增加我们的 对生物过程的理解。更具体地说，我们将推行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和 染色质纤维作为表观遗传基因调控的手段。第二，我们将研究密钥的机制 细菌中的毒力因素，包括它们如何从宿主那里获取铁以及它们如何防御 从多肽仿生学中脱颖而出。最后，我们将开发更有效的计算方法 模拟不同生物分子络合物的溶液小角X射线散射实验结果。 这些研究的完成将揭示关于结构和结构之间关系的复杂细节， 多组分生物分子复合体在广泛的时间和长度范围内的功能和动力学 比例。此外，科学目标之间的协同，以及计算方法和 在每个项目中进行强有力的试验性合作，将培育新的机会和领域 Mira奖将允许我们从事的科学研究。总体而言，这项工作将解决一系列 关键生物过程知识的根本差距，并将为未来奠定基础 将改善人类疾病的治疗和预防的研究。

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.