MOLSImage: Combining Simulations and Imaging to Deliver Next Generation Tools for Studying Bacterial Cell Envelopes.

MOLSImage：结合模拟和成像，提供用于研究细菌细胞包膜的下一代工具。

• 批准号: EP/V030779/1
• 负责人: Syma Khalid
• 金额: $ 186.67万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FV030779%2F1
• 关键词: MOLSImage; Combining; Simulations; Imaging; Deliver

Bacteria are much smaller and simpler organisms than us; they only have one cell. Yet we still do not understand how they function. In particular it is frustrating that we do not understand how they are able to protect themselves from antibiotics - and indeed this is one of the main impediments to the rational development of effective novel antibiotics. Gram-negative bacteria are surrounded by a cell envelope which protects the cell and acts as a filter for the movement of molecules into and out of the cell; waste molecules are allowed to exit, essential nutrients are allowed to enter, whereas harmful molecules are by and large kept out. Currently we do not understand how this is achieved at the level of individual molecules let alone atoms. The MOLSimage programme aims to develop a detailed understanding of the cell envelope that protects bacteria- this is of interest from a fundamental biophysics perspective, but also for the future will be important for developing new antibiotics. We will employ computational methods in combination with new advances in imaging technology being pioneered in the UK, to study the cell envelope in as much detail as possible. Rather than use the current approach of studying individual proteins or small groups of proteins, we will study realistically crowded systems to capture all of the relevant details. The combination of computational and experimental will be such that as increasing computing power becomes available, increasingly larger portions of the cell envelope will become tractable. Our methods will take the snapshots in time produced by the imaging methods, interpret and augment them such that additional molecules (that are too small to be picked up the imaging) are added and then the snapshot is subjected to molecular dynamics for time evolution of the systems. The protocols and methods we develop will firmly place the UK in a world-leading position in terms of studying bacterial cell envelopes.

细菌比我们小得多，也更简单；它们只有一个细胞。然而，我们仍然不了解它们是如何发挥作用的。特别是，令人沮丧的是，我们不理解他们如何能够保护自己免受抗生素的伤害--事实上，这是合理开发有效的新型抗生素的主要障碍之一。革兰氏阴性细菌被一个细胞膜包裹着，它保护细胞，充当分子进出细胞的过滤器；废物分子被允许离开，必要的营养物质被允许进入，而有害分子基本上被挡在门外。目前，我们还不知道这是如何在单个分子的水平上实现的，更不用说原子了。MOLSImage计划旨在详细了解保护细菌的细胞膜--这从基本生物物理学的角度来看是有意义的，但对于未来开发新的抗生素也是重要的。我们将使用计算方法，结合英国开创的成像技术的新进展，尽可能详细地研究细胞包膜。我们不会使用目前研究单个蛋白质或一小群蛋白质的方法，而是研究现实中拥挤的系统，以捕捉所有相关的细节。计算和实验的结合将是这样的，随着计算能力的增加，细胞包膜中越来越大的部分将变得容易处理。我们的方法将及时拍摄成像方法产生的快照，解释并增强它们，以便添加额外的分子(太小而无法拾取成像)，然后对快照进行分子动力学研究，以了解系统的时间演化。我们开发的方案和方法将使英国在研究细菌细胞膜方面牢牢处于世界领先地位。

项目成果

Conformational dynamics and putative substrate extrusion pathways of the N -glycosylated outer membrane factor CmeC from Campylobacter jejuni

空肠弯曲杆菌 N-糖基化外膜因子 CmeC 的构象动力学和假定底物挤出途径

• DOI: 10.1101/2022.08.31.506067
• 发表时间: 2022
• 作者: Newman K

Structural basis for bacterial energy extraction from atmospheric hydrogen.

• DOI: 10.1038/s41586-023-05781-7
• 发表时间: 2023-03
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Grinter, Rhys;Kropp, Ashleigh;Venugopal, Hari;Senger, Moritz;Badley, Jack;Cabotaje, Princess R.;Jia, Ruyu;Duan, Zehui;Huang, Ping;Stripp, Sven T.;Barlow, Christopher K.;Belousoff, Matthew;Shafaat, Hannah S.;Cook, Gregory M.;Schittenhelm, Ralf B.;Vincent, Kylie A.;Khalid, Syma;Berggren, Gustav;Greening, Chris
• 通讯作者: Greening, Chris

A novel fold for acyltransferase-3 (AT3) proteins provides a framework for transmembrane acyl-group transfer.

• DOI: 10.7554/elife.81547
• 发表时间: 2023-01-11
• 期刊: eLife
• 影响因子: 7.7
• 作者: Newman KE;Tindall SN;Mader SL;Khalid S;Thomas GH;Van Der Woude MW
• 通讯作者: Van Der Woude MW

Conformational dynamics and putative substrate extrusion pathways of the N-glycosylated outer membrane factor CmeC from Campylobacter jejuni.

从弯曲杆菌空肠杆菌的N-糖基化外膜CMEC CMEC的构象动力学和推定的底物挤出途径。

• DOI: 10.1371/journal.pcbi.1010841
• 发表时间: 2023-01
• 期刊: PLOS COMPUTATIONAL BIOLOGY
• 影响因子: 4.3
• 作者: Newman, Kahlan;Khalid, Syma
• 通讯作者: Khalid, Syma

Dual function of OmpM as outer membrane tether and nutrient uptake channel in diderm Firmicutes.

• DOI: 10.1038/s41467-023-42601-y
• 发表时间: 2023-11-06
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Silale, Augustinas;Zhu, Yiling;Witwinowski, Jerzy;Smith, Robert E.;Newman, Kahlan E.;Bhamidimarri, Satya P.;Basle, Arnaud;Khalid, Syma;Beloin, Christophe;Gribaldo, Simonetta;van den Berg, Bert
• 通讯作者: van den Berg, Bert