Vaiwala Rakesh, Sharma Pradyumn, Puranik Mrinalini, Ayappa K Ganapathy
Department of Chemical Engineering, Indian Institute of Science, Bangalore 560012, India.
Unilever Research & Development, 64 Main Road, Whitefield, Bangalore 560066, India.
J Chem Theory Comput. 2020 Aug 11;16(8):5369-5384. doi: 10.1021/acs.jctc.0c00539. Epub 2020 Jul 27.
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. [ , , 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 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.
革兰氏阴性菌的细菌细胞包膜是一个复杂的生物屏障，由多层结构组成，包括内膜、肽聚糖周质以及带有脂多糖（LPS）的外膜。随着抗菌耐药性的不断上升，人们越来越关注小分子与细胞膜的相互作用，以助力新型药物分子的研发。因此，需要合适的细菌膜表示方法来进行有意义的分子动力学模拟。鉴于细胞包膜的复杂性，用显式溶剂对细胞膜进行完全原子描述在计算上是难以实现的，只能在小系统规模下进行有限的采样。然而，诸如MARTINI之类的粗粒度（CG）模型使人们能够在生理相关的长度和时间尺度上研究各种现象。尽管文献中已有脂质和LPS的MARTINI模型，但缺乏合适的肽聚糖CG模型。我们利用Gumbart等人描述的全原子模型[ ， ，e1003475]，在MARTINI框架内开发了肽聚糖网络的CG模型。该模型经过参数化处理，以重现聚糖链的端到端距离。其结构特性，如沿链相邻肽段之间的平衡角度、每个二糖的面积以及腔尺寸分布，与原子模拟结果吻合良好。诸如面积压缩性和弯曲模量等力学特性也能被准确重现。在开发新型抗生素时，评估肽聚糖网络的屏障特性很重要。我们使用伞形采样在MARTINI和全原子肽聚糖模型上评估并比较了百里酚分子的插入自由能。结果发现，MARTINI模型和全原子模型的插入自由能均小于 。额外的无约束模拟显示百里酚能快速穿过肽聚糖。我们预计，所提出的肽聚糖MARTINI模型将有助于在更大的长度和时间尺度上理解与细菌细胞壁相关的现象，从而克服当前全原子模型的局限性。
