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

细菌是比我们小得多、简单得多的有机体，它们只有一个细胞。然而，我们仍然不知道它们是如何运作的。特别令人沮丧的是，我们不明白它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。革兰氏阴性菌被细胞膜包围，细胞膜保护细胞并作为分子进出细胞的过滤器;废物分子被允许离开，必需营养素被允许进入，而有害分子基本上被排除在外。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包膜-从基本生物物理学的角度来看，这是令人感兴趣的，但对于未来开发新抗生素也很重要。我们将采用计算方法，结合英国首创的成像技术的新进展，尽可能详细地研究细胞包膜。我们将研究现实的拥挤系统，以捕捉所有相关的细节，而不是使用目前研究单个蛋白质或蛋白质小组的方法。计算和实验的结合将是这样的，随着越来越多的计算能力变得可用，越来越大的部分细胞包络将变得易于处理。我们的方法将及时拍摄由成像方法产生的快照，解释并增强它们，使得添加额外的分子（太小而不能被成像拾取），然后将快照进行分子动力学以用于系统的时间演化。我们开发的协议和方法将使英国在研究细菌细胞包膜方面处于世界领先地位。

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.