COMBATING INFECTION THROUGH ATOMIC-SCALE MODELING OF UNIQUE BACTERIAL SYSTEMS

描述（由申请人提供）：传染病是世界上第二大死亡原因。由于新型抗生素药物几乎不存在，病原菌对当前抗生素的耐药性迅速增加，开发新方法对于促进人类健康工作至关重要。分子建模将在这些新方法中发挥重要作用，因为抗菌剂和耐药机制的关键结构、过程和相互作用的基本原子尺度性质。为了阐明这些结构和过程，PI将专注于细菌特有的和必不可少的三个系统：细菌细胞壁，外膜和SecA蛋白转位酶。细胞壁为细菌提供形状和强度，并且是典型的抗菌靶标，但其介观结构仍然未知。在第一个目标中，将模拟合成细胞壁的酶与其底层组分的相互作用，从而允许开发也可以克服耐药性的新型抗菌剂。在革兰氏阴性细菌中，外膜位于细胞壁之外，是药物分子进入的最大屏障之一。此外，通过现有的蛋白质通道调节少数可用的进入途径，它在药物疗效中起着至关重要的作用。在第二个目标中，PI将量化 这种调节及其对药物流入的影响。最后，在第三个目标中，PI将确定 SecA是一种ATP驱动的马达，能够使新生蛋白质跨膜转运。通过使用该过程中产生的结构数据，SecA将被开发为一种新的抗菌靶标。所有目标都依赖于先进的计算工具和方法，包括尖端的分子动力学模拟。这些模拟提供了跨越各种长度和时间尺度的动态视图，特别是通过千万亿次超级计算资源和充分利用它们所需的软件的出现。

DESCRIPTION (provided by applicant): Infectious diseases are the second leading cause of death in the world. With novel classes of antibiotic drugs virtually nonexistent, and the resistance of pathogenic bacteria to current ones increasing rapidly, the development of new approaches is becoming an imperative for advancing human health efforts. Molecular modeling will play an essential role in these new approaches, due to the fundamentally atomic-scale nature of the critical structures, processes, and interactions underlying the action of both antibacterial agents and resistance mechanisms. In order to illuminate these structures and processes, the PI will focus on three systems specific and essential to bacteria: the bacterial cel wall, the outer membrane, and the SecA protein translocase. The cell wall provides shape and strength to bacteria, and is a canonical antibacterial target, yet its mesoscale structure remains unknown. In the first aim, the interaction of the enzymes synthesizing the cell wall with its underlying components will be modeled, permitting novel antibacterial agents that can also overcome drug resistance to be developed. In Gram-negative bacteria, the outer membrane rests beyond the cell wall and presents one of the greatest barriers to the entry of drug molecules. Furthermore, by modulating the few available entry pathways through existing protein channels, it plays a crucial role in drug efficacy. In the second aim, the PI will quantify this modulation and its effect on drug influx. Finally, in the third aim, the PI will determine the functional cycle of SecA, an ATP driven motor that enables the translocation of nascent proteins across membranes. By using structural data generated in the process, SecA will be exploited as a novel antibacterial target. All aims rely on advanced computational tools and methods, including cutting-edge molecular dynamics simulations. These simulations, which furnish dynamic views spanning a wide range of length and time scales, are enabled, in particular, by the emergence of petascale supercomputing resources and the software necessary to take full advantage of them.