Bridging Disparate Structural/Functional Scales: Multiscale Modeling of the Chromatin Fiber and RNA Tertiary Structures

桥接不同的结构/功能尺度：染色质纤维和 RNA 三级结构的多尺度建模

• 批准号: 10220065
• 负责人: Tamar Schlick
• 金额: $ 46.95万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220065
• 关键词: Affect; Area; Atlases; Biological; Biology; Biophysics; Cell Differentiation process; Cells; Cellular Structures; Chemistry; Chromatin; Chromatin Fiber; Chromatin Loop; Chromatin Structure; Chromosome Structures; Collaborations; Communities; Complex; Computational Biology; Computing Methodologies; Degenerative Disorder; Development; Diagnosis; Engineering; Environment; Epigenetic Process; Gene Expression; Gene Silencing; Genes; Genetic; Genetic Diseases; Genetic Materials; Genome; Grain; Graph; Higher Order Chromatin Structure; Link; Malignant Neoplasms; Maps; Mathematics; Medicine; Methods; Modeling; Molecular; Molecular Computations; Nanotechnology; National Institute of General Medical Sciences; Nucleic Acids; Nucleosomes; Polymers; Process; Property; Protein Binding Domain; Proteins; RNA; RNA Folding; RNA-Binding Proteins; Repression; Sampling; Structure; Structure-Activity Relationship; Syndrome; Technology; Transcriptional Activation; Work; cancer cell; cancer genetics; cancer therapy; computer science; data mining; design; experimental study; genome-wide; graph theory; human disease; improved; innovation; macromolecule; molecular modeling; multi-scale modeling; novel; programs; sensor; targeted treatment

Abstract Advances in both experimental and computational biology are helping make exciting discoveries in many fields of biology and biomedicine today. Together, physical experiments and modeling are solving fundamental puzzles in biology as well as applying the findings to medicine and technology through molecular design, targeted therapies, and nanotechnology. The PI's computational biology /biophysics lab focuses on solving fundamental structural and dynamical questions concerning nucleic acids and their complexes (notably chromatin and RNA) in collaboration with experimentalists by innovative molecular models and computational methods using ideas from mathematics, computer science, and engineering, as well as biology and chemistry. This MIRA project would consolidate three NIGMS projects on chromatin structure, RNA design, and RNA structure prediction to advance our fundamental understanding of structure/function relationships for chromatin and RNA using multiscale models that bridge disparate scales to allow unprecedented applications regarding chromatin and RNA folding. For chromatin, the detailed atomic information on nucleosomes and long-range contact maps available from genome-wide experiments will be bridged by a hierarchy of tunable coarse-grained models to link atomic, mesoscale, and polymer models to investigate the epigenetic modulation of chromatin higher-order structure by gene looping mechanisms in cancer cells; these structural mechanisms for repression/ activation of transcription have translational ramifications through targeted re-expression of those silenced genes by chromatin loop dissolution for cancer therapy. For RNA, the general problem of poor predictions of RNA and RNA/protein tertiary motifs will be tackled by exploiting the drastic variable reduction and natural modularity of 2D graphs to combine efficient coarse-grained graph sampling, graph theory substructuring, and data-mining with improved handling of pseudoknots, kink-turns, and RNA-protein-binding motifs in our program RAGTOP. We will contribute to community efforts like RNA-puzzles; design novel RNAs for predicted, but yet undiscovered, RNA-like fold motifs to produce a atlas of modules for design; and design riboswitches with desired fluorescent properties, as sensors. These works, with support from leading experts in chromatin and RNA structure and function, will help advance fundamental areas of biology /biomedicine including genome biophysics, chromatin higher-order structure, gene expression, and cell development and differentiation and hence the targeted treatment of human diseases associated with aberrant gene expression, including cancers, genetic disorders, and degenerative diseases. The resulting multiscale computing paradigms are widely applicable to other biomolecular processes and will be shared with the community at large.

抽象的 实验生物学和计算生物学的进步正在帮助当今生物学和生物医学的许多领域取得令人兴奋的发现。物理实验和建模共同解决了生物学中的基本难题，并通过分子设计、靶向治疗和纳米技术将研究结果应用于医学和技术。 PI 的计算生物学/生物物理学实验室致力于与实验人员合作，利用数学、计算机科学、工程学以及生物学和化学的思想，通过创新的分子模型和计算方法来解决有关核酸及其复合物（特别是染色质和 RNA）的基本结构和动力学问题。该 MIRA 项目将整合关于染色质结构、RNA 设计和 RNA 结构预测的三个 NIGMS 项目，以促进我们对染色质和 RNA 的结构/功能关系的基本理解，使用桥接不同尺度的多尺度模型，从而实现染色质和 RNA 折叠方面前所未有的应用。对于染色质，从全基因组实验中获得的核小体和远程接触图的详细原子信息将通过可调谐粗粒度模型的层次结构来桥接，以连接原子、介观尺度和聚合物模型，以研究癌细胞中基因循环机制对染色质高阶结构的表观遗传调节；这些抑制/激活转录的结构机制通过染色质环溶解来靶向重新表达那些沉默的基因，从而产生翻译后果，用于癌症治疗。对于RNA，RNA和RNA/蛋白质三级基序预测不佳的普遍问题将通过利用二维图的大幅变量减少和自然模块化来解决，将有效的粗粒度图采样、图论子结构和数据挖掘与我们的程序RAGTOP中对假结、扭结和RNA-蛋白质结合基序的改进处理相结合。我们将为 RNA 谜题等社区工作做出贡献；为预测但尚未发现的类 RNA 折叠基序设计新颖的 RNA，以生成用于设计的模块图集；并设计具有所需荧光特性的核糖开关作为传感器。这些工作在染色质和RNA结构与功能领域领先专家的支持下，将有助于推进生物学/生物医学的基础领域，包括基因组生物物理学、染色质高阶结构、基因表达以及细胞发育和分化，从而靶向治疗与异常基因表达相关的人类疾病，包括癌症、遗传性疾病和退行性疾病。由此产生的多尺度计算范式广泛适用于其他生物分子过程，并将与整个社区共享。