BlueCryo Image Processing Computing Cluster

在分子水平上对生物分子进行成像以可视化其原子细节对于了解它们在健康和疾病中的功能至关重要。在能够对生物分子成像的技术中，冷冻电子显微镜（cryo-EM）已经成为非常强大的技术。新的直接电子探测器，更好的显微镜和强大的图像处理软件记录与这种新的硬件导致了一个真正的革命冷冻EM。随着这些进展，现在可以通过cryo-EM以近原子分辨率确定大分子结构，揭示重要的分子细节。对分子复合物以及整个细胞甚至组织的高分辨率结构洞察，提供了对生命分子机制的重要理解。直到最近，由于缺乏合适的冷冻显微镜，在西南部还不可能进行高分辨率的冷冻电镜。2017年，我们通过在布里斯托大学开设西南地区高分辨率冷冻EM设施来满足这一未满足的需求，该设施配备了最先进的硬件。这将使我们能够在成功收集数据的情况下每天收集数TB的图像或电影。为了充分利用该设施的潜力，并保持和提高我们的竞争态势，我们必须用同样强大的高性能计算（HPC）来补充最先进的冷冻显微镜。TB级图像的处理是如此的计算密集，现有的HPC基础设施无法满足新EM用户社区的计算需求。因此，为了解决这个瓶颈，我们在这里要求资助一个专门用于低温EM数据集图像处理的计算集群（BlueCryo）。BlueCryo将使布里斯托大学的研究人员能够通过单粒子cryo-EM和断层扫描来确定重要的结构，使用尖端的分子建模来解释这些结构，并通过最先进的模拟方法来分析生物系统的功能动力学。BlueCryo HPC集群将支持许多研究人员的工作，以加速他们雄心勃勃的研究，其中许多研究由BBSRC资助。新的资源将有助于发现基因表达的新机制，研究蛋白质转运进入和穿过膜，了解在细菌感染中起关键作用的分泌系统的机制，并阐明负责我们细胞中生物功能（和故障）的其他重要分子过程。此外，HPC集群将在疫苗学、药物递送和药物发现方面为具有定制功能的全新蛋白质和肽组装的合理设计提供关键支持。重要的是，新的BlueCryo计算资源与冷冻显微镜一起，将进一步吸引来自不同生命科学领域的研究人员参与冷冻EM革命，并在西南部及其他地区产生新的令人兴奋的研究协同效应。我们的工作对BBSRC职权范围内的多个领域具有广泛的影响，包括合成生物学，支持正常人类和动物健康和感染的基础生物科学。这些项目涵盖与BBSRC职权范围和战略直接相关的领域。该提案包括具有BBSRC资助良好记录的研究人员。早期的职业研究人员和一个重新进入研究员是我们团队的一部分。显然，计算集群不仅将决定性地推进这里提出的研究，并产生新的方案、协同作用和合作。它还将使我们能够参与许多其他重要的科学问题，并培训新的用户和学生。因此，我们希望在布里斯托大学的基础和应用研究的许多领域获得显着的额外使用，西南及其他地区。

Imaging biomolecules at the molecular level to visualize their atomic details is essential to understand how they function in health and disease. Among the techniques capable of imaging biomolecules, electron cryo-microscopy (cryo-EM) has emerged as exceptionally powerful. New direct electron detectors, better microscopes and powerful processing software for the images recorded with this new hardware has led to a genuine revolution in cryo-EM. With these advances it is now possible to determine macromolecular structures at near-atomic resolution by cryo-EM, revealing essential molecular detail. High-resolution structural insight into molecular complexes, and also entire cells and even tissues, provide vital understanding of the molecular mechanisms of life. Until recently, high-resolution cryo-EM was not possible in the South-West due to the lack of a suitable cryo-microscope. In 2017, we answer this unmet need by opening a South West Regional Facility for High-Resolution Cryo-EM at University of Bristol, equipped with state-of-the-art hardware. This will enable us to collect several terabytes of images or movies per day of successful data collection. To fully exploit the potential of this facility, and to maintain and increase our competitive posture, we must complement the state-of-the-art cryo-microscope with equally powerful high-performance computing (HPC) for image processing. Processing of the terabytes of images is so computation-intense that existing HPC infrastructure can by no means match the computation requirements of the new EM user community.Therefore, to resolve this bottleneck, we ask here for funding of a computing cluster dedicated to image processing of cryo-EM data sets (BlueCryo). BlueCryo will enable researchers at University of Bristol to determine important structures by single particle cryo-EM and tomography, to interpret these structures using cutting-edge molecular modelling and to analyse the functional dynamics of the biological systems by state-of-the-art simulation methods. The BlueCryo HPC cluster will support the work of many researchers to accelerate their ambitious research, many of them funded by the BBSRC. The new resource will be instrumental for the discovery of new mechanisms of gene expression, to study protein transport into and across membranes, to understand the mechanism of secretion systems which play a crucial role in bacterial infections, and to illuminate a wide range of other important molecular processes responsible for biological function (and malfunction) in our cells. Moreover, the HPC cluster will critically support rational design of entirely novel proteins and peptide assemblies with tailor-made function, in vaccinology, drug delivery and drug discovery. Importantly, the new BlueCryo computing resource, together with the cryo-microscope, will further entice researchers from diverse life-science areas to partake in the cryo-EM revolution and generate new and exciting research synergies all across the South-West and beyond.Our work has broad implications for multiple areas within the BBSRC remit including synthetic biology, basic bioscience underpinning normal human and animal health and infection. The projects cover areas of direct relevance to BBSRC remit and strategy. The proposal includes researchers with a strong track record of BBSRC funding. Early career researchers and a re-entry fellow are part of our team. Clearly, the computing cluster will not only decisively advance the research here proposed, and generate new programmes, synergies and collaborations. It will also enable us to engage in many other important scientific questions and to train new users and students. Thus, we expect to derive significant additional use in many areas of basic and applied research at University of Bristol, the South-West and beyond.