Bridging Disparate Structural/Functional Scales: Multiscale Modeling of Genome Organization and of Viral RNA Frameshifting

摘要 随着实验和计算生物学的进步导致许多fi领域的令人兴奋的发现 在生物学和生物医学的今天，诊断和治疗人类疾病的新途径正在成为现实。 分子动力学和其他模拟方法在这些联系中发挥了关键作用，它们帮助define 潜在的生物物理机制，以前所未有的分辨率。国际和平研究所的计算生物物理实验室 专注于解决有关核酸及其络合物的基本结构和功能挑战 (特别是染色质和RNA)，与实验者合作，通过创新的分子模型和 利用数学、计算机科学、工程学、生物学和化学的思想进行模拟的方法。这 Mira计划将继续促进我们对基因组组织和RNA基序的基本理解 使用连接不同的空间和时间尺度的多尺度模型来生成对 基因组折叠和癌症基因组学，以及RNA构象景观/病毒机制。对于染色质和 染色体、模拟的核小体及其蛋白质复合体在原子分辨率下，以及染色质fi在 中尺度，将与全基因组和癌症表观基因组研究的数据联系起来，以确定调制 在基因异常表达过程中染色质的高阶结构。SPECIfiCally，我们将重点关注 蛋白质(如CTCF和H1)在基因环路和拓扑形成中的结构作用和机制 癌细胞中基因激活或抑制中的相关结构域(TADS)和核间隔区。对于RNA， 我们用粗粒图(RAG：RNA-as-graph)来模拟RNA二级结构的拓扑方法， 结合原子生物物理模型，将描绘出程序化的核糖体移码机制 RNA冠状病毒和其他病毒，并推进RNA基序图谱。SpeciifiCally，构象动力学 与SARS-CoV-2的RNA移框元件相关，以及进化和生物物理分析 和化学反应实验，将描述移码转换，并通过实验识别/测试 可能阻碍移码的结构改变突变。RAG还将应用于define a病毒拓扑 Atlas和从RNA曲目的角度探索病毒基序，以帮助理解RNA基序宇宙 并提出了新颖的RNA设计。基因组组织和RNA的生物物理机制研究进展 移码/构象谱系具有翻译的Ramifi阳离子用于人类癌症和病毒感染 被冠状病毒或艾滋病毒感染。对于癌症治疗，有针对性地重新表达沉默的基因可能是通过 染色质拓扑变化(例如，环溶解)和RNA编辑。针对病毒RNA感染，新策略 从这项研究中出现的基因和抗病毒治疗，通过现代RNA编辑技术是可行的。这个 由此产生的多学科计算范式广泛适用于其他生物分子过程和 将与广大社区共享。

Abstract As advances in both experimental and computational biology lead to exciting discoveries in many fields of biology and biomedicine today, new avenues to diagnose and treat human disease are becoming a reality. Molecular dynamics and other simulation approaches play a key role in these connections by helping define the underlying biophysical mechanisms, at unprecedented resolution. The PI's computational biophysics lab focuses on solving fundamental structural and functional challenges concerning nucleic acids and their complexes (notably chromatin and RNA), in collaboration with experimentalists, by innovative molecular models and simulation methods using ideas from mathematics, computer science, engineering, biology, and chemistry. This MIRA project would continue to advance our fundamental understanding of genome organization and RNA motifs using multiscale models that bridge disparate spatial and temporal scales to generate biophysical insights into genome folding and cancer genomics, and RNA conformational landscapes/ viral mechanisms. For chromatin and chromosomes, modeled nucleosomes and their protein complexes at atomic resolution, and chromatin fibers at the mesoscale, will be linked to data from genome-wide and cancer epigenomics studies to determine the modulation of chromatin higher-order structure in processes of aberrant gene expression. Specifically, we will focus on the structural role and mechanisms of proteins (like CTCF and H1) in gene looping and formation of topologically associated domains (TADs) and nuclear compartments in gene activation or repression in cancer cells. For RNA, our topological approach to modeling RNA secondary structure by coarse-grained graphs (RAG: RNA-As-Graphs), combined with atomic biophysical modeling, will delineate programmed ribosomal frameshifting mechanisms in RNA coronaviruses and other viruses, and advance the RNA motif atlas. Specifically, conformational dynamics associated with the RNA frameshifting element of SARS-CoV-2, along with evolutionary and biophysical analysis and chemical reactivity experiments, will describe frameshifting transitions and identify/test experimentally structure-altering mutations that may hamper frameshifting. RAG will also be applied to define a virus topology atlas and explore virus motifs from an RNA repertoire point of view, to help understand the RNA motif universe and advance novel RNA design. The unraveled biophysical mechanisms in genome organization and RNA frameshifting/conformational repertoire have translational ramifications for human cancers and viral infections by coronaviruses or HIV. For cancer therapy, a targeted re-expression of silenced genes may be possible by chromatin topological changes (e.g., loop dissolution) and RNA editing. For viral RNA infections, new strategies for gene and anti-viral therapy emerge from this research, feasible by modern RNA editing technologies. The resulting multidisciplinary computational paradigms are widely applicable to other biomolecular processes and will be shared with the community at large.