Atomistic reconstruction of large biomolecular systems from low-resolution cryo-electron microscopy data - RECKON

利用低分辨率冷冻电子显微镜数据原子重建大型生物分子系统 - RECKON

• 批准号: EP/Y010221/1
• 负责人: Dmitry Nerukh
• 金额: $ 23.84万
• 依托单位: Aston University
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY010221%2F1
• 关键词: Atomistic; reconstruction; large; biomolecular; systems

The project's aim is to develop a ready-to-use technique for all-atom structure reconstruction of biomolecules using poorly resolved cryo-electron microscopy (cryo-EM) data. The objectives include developing an intelligent protocol for dealing with low-resolution cryo-EM density, developing a toolkit of scripts or software modules for facilitating the process, and producing all-atom structure of a bacteriophage from newly-acquired cryo-EM data. The problem is highly relevant because the amount of published cryo-EM data growth rapidly, especially of large biomolecular objects such as whole viruses. Methodologies of reconstructing molecular structures from these data lag far behind. This strongly limits scientific output of such elaborate and expensive experiments. The ultimate goal of a cryo-EM experiment is an atomistic model of the target that can form the basis for further biochemical research. Currently, the goal can only be achieved if the collected cryo-EM density has high enough resolution to apply the existing reconstruction algorithms. However, often large regions with low resolution are present due to either instrumental or fundamental limitations, making commonly used algorithms to fail.Our methodology takes additional information on the target into account (chemical structure, biomolecular constraints, etc) in the reconstruction process. The intelligent algorithm to be developed will be able to deal with previously inaccessible regions of cryo-EM data and thus make it possible to reconstruct the target in its atomistic completeness. To test it, a cryo-EM measurement of a Qbeta bacteriophage will be done, which is an important biological target. The produced all-atom model of genome-loaded phage will be of high interest for virologists and molecular biologists, and the technique itself will attract attention of research groups specialising in cryo-EM, including industry.

该项目的目标是开发一种易于使用的技术，利用分辨率较差的冷冻电子显微镜(Cryo-EM)数据重建生物分子的全原子结构。目标包括开发处理低分辨率低温EM密度的智能方案，开发促进这一过程的脚本或软件模块工具包，以及从新获得的低温EM数据中产生全原子结构的噬菌体。这个问题是高度相关的，因为发表的低温电磁数据的数量迅速增长，特别是整个病毒等大型生物分子对象的数据量。从这些数据重建分子结构的方法远远落后。这严重限制了这种复杂而昂贵的实验的科学产出。低温电磁实验的最终目标是建立目标的原子模型，为进一步的生物化学研究奠定基础。目前，只有当收集到的低温电磁密度具有足够高的分辨率来应用现有的重建算法时，才能实现这一目标。然而，由于仪器或基础的限制，通常存在较大的低分辨率区域，使得常用的算法失败。我们的方法在重建过程中考虑到关于目标的额外信息(化学结构、生物分子约束等)。将要开发的智能算法将能够处理以前无法访问的低温电磁数据区域，从而使以原子完整性重建目标成为可能。为了测试它，将对Qbeta噬菌体进行冷冻EM测量，这是一个重要的生物目标。生产的全原子基因组噬菌体模型将引起病毒学家和分子生物学家的高度兴趣，该技术本身将吸引专门从事低温EM研究的研究小组的注意，包括工业。