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Modeling and design of complex RNA structures

复杂 RNA 结构的建模和设计

基本信息

批准号：
10685534
负责人：
Rhiju Das
金额：
$ 68.47万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2027-07-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY The continuing discoveries of RNAs and their critical roles in cellular and viral machinery are inspiring novel antibacterial, antitumor, antiviral, and genome-editing therapies based on disabling, manipulating, and repurposing the RNAs involved. Unfortunately, our poor biophysical understanding of `how RNAs work' is slowing the development of these potentially life-saving efforts. A critical bottleneck has been the inapplicability of crystallography, NMR, phylogenetic analysis, and biochemical methods to determine the partly ordered conformations of non-coding RNAs in all their functional states. To address this bottleneck, we bring together biophysical modeling, electron microscopy, high throughput biochemical/sequencing experiments, machine learning, wet-lab- integrated crowdsourcing, and a wide collaborative network. Current projects that exemplify our approach involve the COVID-19 pandemic. With our Ribosolve hybrid structure determination pipeline, we are discovering that numerous segments of the SARS-CoV-2 RNA genome form well-defined 3D structures whose targeting by antisense oligonucleotides inhibits viral replication. In the OpenVaccine challenge, we are developing highly structured COVID-19 mRNA vaccines with sufficient in vitro stability to enable world-wide shipping of mRNA in prefilled syringes. This COVID-19 research has benefited from our agile approach and the flexibility allowed by MIRA support; many of the computational and experimental methods we use now did not exist before the pandemic. Because RNA is so fundamental to life, tackling many of science's further `big questions' in human disease could be accelerated if we could visualize and design any RNA. My lab seeks to create the RNA computational and experimental foundation needed to get all of us there in upcoming years.

项目摘要 RNA的不断发现及其在细胞和病毒机制中的关键作用正在激发新的抗菌，抗肿瘤，抗病毒和基因组编辑疗法基于禁用、操纵和重新利用相关的RNA。不幸的是，我们对“RNA如何工作”的生物物理理解不足，这些潜在的拯救生命的努力。一个关键的瓶颈是，晶体学，核磁共振，系统发育分析和生物化学方法来确定非编码RNA在其所有功能状态下的部分有序构象。到为了解决这个瓶颈，我们将生物物理模型，电子显微镜，高通量生物化学/测序实验，机器学习，湿实验室，综合众包和广泛的合作网络。目前的项目，我们的方针涉及COVID-19疫情。我们的Ribosolve混合动力结构确定管道，我们发现， SARS-CoV-2 RNA基因组形成定义明确的3D结构，反义寡核苷酸抑制病毒复制。在OpenVaccine挑战赛中，我们正在开发高度结构化的COVID-19 mRNA疫苗，稳定性，以使mRNA在预充式注射器中的全球运输成为可能。COVID-19 研究受益于我们的敏捷方法和MIRA允许的灵活性支持;我们现在使用的许多计算和实验方法都不存在在大流行之前。因为RNA是生命的基础，解决了许多科学上的如果我们能够想象和研究人类疾病中的其他“大问题”，设计任何RNA。我的实验室致力于创造RNA的计算和实验基金会需要在未来几年让我们所有人都能实现这一目标。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Using Rosetta for RNA homology modeling.

DOI：
10.1016/bs.mie.2019.05.026
发表时间：
2019
期刊：
Methods in enzymology
影响因子：
0
作者：
Watkins AM;Rangan R;Das R
通讯作者：
Das R

RNA secondary structure packages evaluated and improved by high-throughput experiments.

DOI：
10.1038/s41592-022-01605-0
发表时间：
2022-10
期刊：
NATURE METHODS
影响因子：
48
作者：
Wayment-Steele, Hannah K.;Kladwang, Wipapat;Strom, Alexandra I.;Lee, Jeehyung;Treuille, Adrien;Becka, Alex;Das, Rhiju
通讯作者：
Das, Rhiju

Learning RNA structure prediction from crowd-designed RNAs.

DOI：
10.1038/s41592-022-01607-y
发表时间：
2022-10
期刊：
NATURE METHODS
影响因子：
48
作者：
Wayment-Steele, Hannah K.;Das, Rhiju
通讯作者：
Das, Rhiju

Three-dimensional structure-guided evolution of a ribosome with tethered subunits.

DOI：
10.1038/s41589-022-01064-w
发表时间：
2022-09
期刊：
NATURE CHEMICAL BIOLOGY
影响因子：
14.8
作者：
Kim, Do Soon;Watkins, Andrew;Bidstrup, Erik;Lee, Joongoo;Topkar, Ved;Kofman, Camila;Schwarz, Kevin J.;Liu, Yan;Pintilie, Grigore;Roney, Emily;Das, Rhiju;Jewett, Michael C.
通讯作者：
Jewett, Michael C.

How to Kinetically Dissect an RNA Machine.