Microbiology and Systems Biology focusing on computational microbiology

这项工作计划集中于使用建模和分子模拟来表征噬菌体-细菌相互作用的各个方面。病原菌由于对目前大多数抗生素的耐药性，仍然是人类、动物和植物福利的一个巨大问题。包围革兰氏阴性细菌的细胞膜由两层膜(内膜和外膜)组成，这两层膜被称为周质的水溶液区域隔开。这三个区域一起为细菌提供了一种强大的防御系统，以抵御包括抗生素在内的不必要的外来分子。近年来，噬菌体是细菌的天然捕食者，有可能被用于治疗目的，这一点已经变得很明显。在这个项目中，基于最近在结构生物学和分子模拟以及噬菌体蛋白与其细菌膜受体复合体的动力学方面的工作，我们将解决以下开放的问题：1-细菌外膜受体如何通过长的O-抗原链与噬菌体结合？2-噬菌体蛋白的结合如何改变受体蛋白的构象动力学？3-天然的内毒素-噬菌体蛋白相互作用的性质是什么？这些在细菌物种中有何不同？学生获得的技能：使用传统和基于人工智能的方法进行分子建模。2级分辨率的分子模拟。在一系列高性能计算体系结构上运行模拟的经验。与结构生物学家合作并阐明MRC战略技能优先事项的能力：定量技能，特别是在模拟数据分析、确定轨迹的收敛和识别保守的分子相互作用方面。具有解释结构数据和结合模型构建仿真系统的跨学科技能

This programme of work focusses on using modelling and molecular simulations to characterise various aspects of bacteriophage-bacteria interactions.Pathogenic bacteria remain an enormous problem for human, animal and plant welfare due to their resistance to most current antibiotics. The cell envelope that surrounds Gram-negative bacteria is composed of two membranes (the inner and outer) which are separated by an aqueous region known as the periplasm. Together these three regions provide the bacterium with a formidable defence against unwanted incoming molecules, including antibiotics. In recent years it has become apparent that bacteriophages, which are natural predators of bacteria have the potential to be co-opted for therapeutic purposes. In this project, building upon recent work in structural biology and molecular modelling and dynamics of bacteriophage proteins in complex with their bacterial membrane receptors, we will address the following open questions:1- How accessible are bacterial outer membrane receptors to the bacteriophage through the long O-antigen chains of lipopolysaccharide (LPS)?2- How does the binding of the bacteriophage protein alter the conformational dynamics of the receptor protein?3- What are the nature of the native LPS-bacteriophage proteins interactions? How do these vary across bacterial species?Skills gained by the student:Molecular modelling using traditional and AI-based methods.Molecular simulations at > 2 levels of resolution.Experience of running simulations on a range of High-Performance Computing architectures.The ability to collaborate with structural biologists and to articulateMRC strategic skill priorities:Quantitative skills, particularly in analysis of simulation data, determining convergence of trajectories and identifying conserved molecular interactions. Interdisciplinary skills in interpreting structural data and integrating with models to construct simulation systems