The Energy Landscape for Folding and Function of Biomolecules: From Proteins to Chromatin

该项目的重点是开发模型，以探索染色质结构和动力学，以及蛋白质复合物组装。染色质是构成细菌以外的生物体的染色体的物质。该项目将创建研究不同物种和细胞周期阶段的基因组组织所需的计算模型。在生物分子水平上，该项目将整合结构模型和计算机模拟，以了解大型生物分子复合物（如染色质）的结构，动力学和功能。该项目的更广泛的影响包括蛋白质和染色质折叠，动力学和功能的公开可用的软件/网络服务器的开发。 还强调培训，特别是来自代表性不足群体的学生的培训。为了实现项目目标，将开发模型来探索染色质结构和动力学以及蛋白质复合物组装。在基因组结构研究中，最小染色质模型（MiChroM）将被扩展以确定适应几个不同物种所需的新参数。除了目前针对间期染色体优化的参数之外，还需要新的参数来探索从间期到中期的整个细胞周期的染色体结构集合。这些模型的预测将根据显微镜数据进行验证。此外，全细胞核模拟将研究在所有其他染色体的背景下的染色体系综，以及核纤层-染色质相互作用的影响。目前的染色质模型将被推广到不仅仅是几种类型和亚型，并使用完全通用的能量函数预测这些染色体3D结构集合; Hi-C数据的直接反演。这样的推广将需要理解的功能，目前没有考虑标准MiChroM和调查的物种，显示其染色体结构上的小隔间形成的基因组。该项目的第二个方面将是使用基于结构的模型（SBM）和直接耦合分析（DCA）相结合来预测其全局结构和功能景观的大型蛋白质复合物的研究。这些结果将与物理模拟，需要了解详细的本地结构构象和定量预测这些构象之间的转换的能量。虽然这项研究将集中在结构维持染色体（SMC）蛋白复合物和SARS-CoV-2中的Spyke蛋白，这一策略也可以应用于其他几个大型生物分子系统。该项目由物理学系的生命系统物理学和分子与细胞生物科学系的分子生物物理学小组资助。该奖项反映了NSF的法定使命，并被认为是通过使用基金会的知识价值和更广泛的影响审查标准进行评估，

This project focuses on developing models to explore chromatin structure and dynamics, and protein complex assembly. Chromatin is the material of which the chromosomes of organisms other than bacteria are composed. This project will create computational models needed to investigate the genome organization in different species and phases of the cell cycle. At the biomolecular level, this project will integrate structural models and computer simulations to understand structure, dynamics, and function of large biomolecular complexes, like chromatin. Broader Impacts of this project include the development of publicly available software/web-servers for protein and chromatin folding, dynamics, and function. Emphasis is also given to training, particularly of students from underrepresented groups.To achieve the project goals, models will be developed to explore chromatin structure and dynamics and protein complex assembly. In the genome architecture research, the Minimal Chromatin Model (MiChroM) will be expanded to determine new parameters necessary to accommodate several different species. Going beyond the current parameters that have been optimized for chromosomes at the interphase, new parameters will be needed to explore chromosome structural ensembles across the cell cycle, going from the interphase through the metaphase. Predictions of these models will be validated against microscopy data. Also, full nucleus simulations will investigate chromosome ensembles in the context of all other chromosomes and also the influence of nuclear lamina-chromatin interactions. The current chromatin model will be generalized to go beyond just a few types and subtypes and predict these chromosome 3D structural ensembles with a completely general energy function; a direct inversion of Hi-C data. Such generalization will be needed to understand features that are not currently considered by standard MiChroM and to investigate genomes of species that show little compartment formation on their chromosomal structures. The second aspect of this project will be on the investigation of large protein complexes using a combination of Structure-Based Models (SBM) and Direct Coupling Analysis (DCA) to predict their global structural and functional landscape. These results will be integrated with physical simulations that are needed to understand detailed energetics of local structural conformations and quantitative predictions of the transitions between these conformations. Although the research will focus on Structural Maintenance Chromosome (SMC) protein complexes and the Spyke protein in SARS-CoV-2, this strategy may also be applied to several other large biomolecular systems.This project is funded by the Physics of Living Systems in the Division of Physics and the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.