Zou Guijin, Liu Yue, Gao Huajian
Institute of High Performance Computing, ASTAR, Singapore 138632, Singapore.
School of Engineering, Brown University, Providence, RI 02912, USA.
Extreme Mech Lett. 2020 Sep;39:100817. doi: 10.1016/j.eml.2020.100817. Epub 2020 Jun 8.
The COVID-19 pandemic has brought infectious diseases again to the forefront of global public health concerns. In this EML webinar (Gao, 2020), we discuss some recent work on simulation-assisted discovery of membrane targeting nanomedicine to counter increasing antimicrobial resistance and potential application of similar ideas to the current pandemic. A recent report led by the world health organization (WHO) warned that 10 million people worldwide could die of bacterial infections each year by 2050. To avert the crisis, membrane targeting antibiotics are drawing increasing attention due to their intrinsic advantage of low resistance development. In collaboration with a number of experimental groups, we show examples of simulation-assisted discovery of molecular agents capable of selectively penetrating and aggregating in bacterial lipid membranes, causing membrane permeability/rupture. Through systematic all-atom molecular dynamics simulations and free energy analysis, we demonstrate that the membrane activity of the molecular agents correlates with their ability to enter, perturb and permeabilize the lipid bilayers. Further study on different cell membranes demonstrates that the selectivity results from the presence of cholesterol in mammalian but not in bacterial membranes, as the cholesterol can condense the hydrophobic region of membrane, preventing the penetration of the molecular agents. Following the molecular penetration, we establish a continuum theory and derive the energetic driving force for the domain aggregation and pore growth on lipid membrane. We show that the energy barrier to membrane pore formation can be significantly lowered through molecular aggregation on a large domain with intrinsic curvature and a sharp interface. The theory is consistent with experimental observations and validated with coarse-grained molecular dynamics simulations of molecular domain aggregation leading to pore formation in a lipid membrane. The mechanistic modelling and simulation provide some fundamental principles on how molecular antimicrobials interact with bacterial membranes and damage them through domain aggregation and pore formation. For treating viral infections and cancer therapy, we discuss potential size- and lipid-type-based selectivity principles for developing membrane active nanomedicine. These studies suggest a general simulation-assisted platform to accelerate discovery and innovation in nanomedicine against infectious diseases. EML Webinar speakers are updated at https://imechanica.org/node/24132.
新冠疫情再次将传染病推到了全球公共卫生关注的前沿。在本次EML网络研讨会（高，2020年）中，我们讨论了一些关于模拟辅助发现靶向膜纳米药物以应对日益增加的抗菌耐药性的近期工作，以及类似理念在当前疫情中的潜在应用。世界卫生组织（WHO）牵头的一份近期报告警告称，到2050年，全球每年可能有1000万人死于细菌感染。为避免这场危机，靶向膜抗生素因其耐药性发展较低的内在优势而受到越来越多的关注。与多个实验小组合作，我们展示了模拟辅助发现能够选择性穿透并聚集在细菌脂质膜中、导致膜通透性/破裂的分子试剂的实例。通过系统的全原子分子动力学模拟和自由能分析，我们证明分子试剂的膜活性与其进入、扰动和通透脂质双层的能力相关。对不同细胞膜的进一步研究表明，选择性源于哺乳动物细胞膜中存在胆固醇而细菌细胞膜中不存在，因为胆固醇会使膜的疏水区域凝聚，阻止分子试剂穿透。在分子穿透之后，我们建立了一个连续介质理论，并推导了脂质膜上域聚集和孔生长的能量驱动力。我们表明，通过在具有固有曲率和尖锐界面的大区域上进行分子聚集，可以显著降低膜孔形成的能量障碍。该理论与实验观察结果一致，并通过脂质膜中分子域聚集导致孔形成的粗粒度分子动力学模拟得到验证。机理建模和模拟提供了一些关于分子抗菌剂如何与细菌膜相互作用并通过域聚集和孔形成对其造成损伤的基本原理。对于治疗病毒感染和癌症治疗，我们讨论了开发膜活性纳米药物基于大小和脂质类型的潜在选择性原则。这些研究提出了一个通用的模拟辅助平台，以加速针对传染病的纳米药物的发现和创新。EML网络研讨会演讲者信息在https://imechanica.org/node/24132上更新。
