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

COVID-19大流行再次将传染病带到了全球公共卫生关注的最前沿。在此EML网络研讨会（高，2020年）中，我们讨论了一些新的研究，这些研究涉及膜靶向纳米药物的模拟辅助发现，以对抗日益增加的抗微生物药耐药性，以及类似观念在当前大流行中的潜在应用。由世界卫生组织（WHO）领导的最新报告警告说，到2050年，全世界每年将有1000万人死于细菌感染。为避免这场危机，膜靶向抗生素由于其低耐药性发展的内在优势而受到越来越多的关注。与许多实验小组合作，我们展示了模拟辅助发现分子剂的实例，这些分子剂能够选择性地渗透和聚集在细菌脂质膜中，从而引起膜通透性/破裂。通过系统的全原子分子动力学模拟和自由能分析，我们证明了分子剂的膜活性与其进入，扰动和透化脂质双层的能力有关。对不同细胞膜的进一步研究表明，选择性的产生是由于哺乳动物中存在胆固醇而不是细菌膜中存在胆固醇，因为胆固醇可以凝结膜的疏水区域，从而阻止分子试剂的渗透。随着分子的渗透，我们建立了一个连续理论，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，通过具有固有曲率和尖锐界面的大域上的分子聚集可以显着降低膜孔形成的能垒。该理论与实验观察结果一致，并通过分子域聚集导致脂质膜中孔形成的粗粒分子动力学模拟得到验证。机理建模和仿真提供了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破坏细菌膜的一些基本原理。为了治疗病毒感染和癌症治疗，我们讨论了潜在的基于大小和脂质类型的选择性原理，用于开发膜活性纳米医学。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医学的发现和创新。

EML网络研讨会演讲者的更新网址为https://imechanica.org/node/24132