The bacterial cell envelope of Gram-negative bacteria is a complex biological barrier with multiple layers consisting of the inner membrane, periplasm of peptidoglycan, and the outer membrane with lipopolysaccharides (LPS). With rising antimicrobial resistance there is increasing interest in understanding interactions of small molecules with the cell membrane to aid in the development of novel drug molecules. Hence suitable representations of the bacterial membrane are required to carry out meaningful molecular dynamics simulations. Given the complexity of the cell envelope, fully atomistic descriptions of the cell membrane with explicit solvent are computationally prohibitive, allowing limited sampling with small system sizes. However, coarse-grained (CG) models such as MARTINI allow one to study phenomena at physiologically relevant length and time scales. Although MARTINI models for lipids and the LPS are available in literature, a suitable CG model of peptidoglycan is lacking. Using an all-atom model described by Gumbart et al. [PLoS Comput. Biol.2014, 10, e1003475], we develop a CG model of the peptidoglycan network within the MARTINI framework. The model is parametrized to reproduce the end-to-end distance of glycan strands. The structural properties such as the equilibrium angle between adjacent peptides along the strands, area per disaccharide, and cavity size distributions agree well with the atomistic simulation results. Mechanical properties such as the area compressibility and the bending modulus are accurately reproduced. While developing novel antibiotics it is important to assess barrier properties of the peptidogylcan network. We evaluate and compare the free energy of insertion for a thymol molecule using umbrella sampling on both the MARTINI and all-atom peptidoglycan models. The insertion free energy was found to be less than k_BT for both the MARTINI and all-atom models. Additional restraint free simulations reveal rapid translocation of thymol across peptidogylcan. We expect that the proposed MARTINI model for peptidoglycan will be useful in understanding phenomena associated with bacterial cell walls at larger length and time scales, thereby overcoming the current limitations of all-atom models.

中文翻译：

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开发用于细菌细胞壁的粗颗粒模型：评估机械性能和自由能壁垒。

革兰氏阴性细菌的细菌细胞被膜是一个复杂的生物屏障，具有多层结构，包括内膜，肽聚糖周质和外膜以及脂多糖（LPS）。随着抗菌素耐药性的提高，人们越来越需要了解小分子与细胞膜的相互作用，以帮助开发新的药物分子。因此，需要细菌膜的适当表示来进行有意义的分子动力学模拟。考虑到细胞包膜的复杂性，用明确的溶剂对细胞膜进行完整的原子描述在计算上是禁止的，从而允许在小系统尺寸下进行有限的采样。然而，像MARTINI这样的粗粒度（CG）模型允许人们在生理相关的长度和时间尺度上研究现象。尽管文献中有关于脂类和LPS的MARTINI模型，但缺乏合适的肽聚糖CG模型。使用Gumbart等人描述的全原子模型。[PLoS计算。生物学 2014年，10，e1003475]，我们在MARTINI框架内开发了肽聚糖网络的CG模型。参数化模型可重现聚糖链的端对端距离。结构特性，如相邻链之间相邻肽段之间的平衡角，每个二糖的面积以及空腔大小分布与原子模拟结果非常吻合。精确地再现了诸如面积可压缩性和弯曲模量的机械性能。在开发新型抗生素时，重要的是评估肽基葡聚糖网络的阻隔性能。我们在MARTINI和全原子肽聚糖模型上使用伞式采样评估并比较了百里香酚分子的插入自由能。发现插入自由能小于k _B T适用于MARTINI和全原子模型。其他不受约束的模拟显示百里香酚跨肽基葡聚糖快速转运。我们希望，拟议的肽聚糖的MARTINI模型将有助于理解与细菌细胞壁相关的更大长度和更大时间尺度的现象，从而克服目前所有原子模型的局限性。