COMBATING INFECTION THROUGH ATOMIC-SCALE MODELING OF UNIQUE BACTERIAL SYSTEMS

通过独特细菌系统的原子尺度建模来对抗感染

• 批准号: 8653533
• 负责人: James C. Gumbart
• 金额: $ 10.75万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653533
• 关键词: Address; Anti-Bacterial Agents; Antibiotics; Bacteria; Bacterial Drug Resistance; Bacterial Infections; Binding; Cause of Death; Cell Wall; Collaborations; Communicable Diseases; Computer software; Computing Methodologies; Data; Development; Diffusion; Drug Design; Drug Receptors; Drug Targeting; Drug resistance; Enzyme Interaction; Enzymes; Goals; Gram-Negative Bacteria; Health; Human; Infection; Intervention; Lead; Length; Lipids; Mediating; Membrane; Modeling; Molecular; Molecular Conformation; Molecular Models; Motor; Nature; Organism; Pathway interactions; Pharmaceutical Preparations; Play; Process; Protein translocation; Proteins; Resistance; Resources; Rest; Role; Shapes; Structure; Supercomputing; System; Therapeutic Intervention; Time; advanced simulation; combat; computerized tools; design; drug discovery; drug efficacy; glycosylation; inhibitor/antagonist; insight; molecular dynamics; molecular modeling; next generation; novel; novel strategies; pathogenic bacteria; resistance mechanism; simulation; translocase; virtual

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.

描述(申请人提供)：传染病是全球第二大致死原因。随着新型抗生素药物的几乎不存在，以及病原菌对现有药物的耐药性迅速增加，开发新的方法正成为推进人类健康努力的当务之急。分子模拟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、过程和相互作用的本质是原子尺度的。为了阐明这些结构和过程，PI将集中在细菌特有的和必不可少的三个系统上：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，是典型的抗菌目标，但其中尺度结构尚不清楚。在第一个目标中，将模拟合成细胞壁的酶与其底层成分的相互作用，从而开发出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障碍之一。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将决定 SECA的功能循环，这是一种由三磷酸腺苷驱动的马达，使新生蛋白质能够跨膜转运。通过使用在此过程中产生的结构数据，SecA将被开发为新的抗菌靶点。所有的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广泛长度和时间范围的动态视图，尤其是由于千万亿级超级计算资源的出现和充分利用这些资源所必需的软件的出现。

项目成果

Thermodynamics of Deca-alanine Folding in Water.

• DOI: 10.1021/ct5002076
• 发表时间: 2014-07-08
• 期刊: JOURNAL OF CHEMICAL THEORY AND COMPUTATION
• 影响因子: 5.5
• 作者: Hazel, Anthony;Chipot, Christophe;Gumbart, James C.
• 通讯作者: Gumbart, James C.

The adaptive biasing force method: everything you always wanted to know but were afraid to ask.

• DOI: 10.1021/jp506633n
• 发表时间: 2015-01-22
• 期刊: The journal of physical chemistry. B
• 作者: Comer J;Gumbart JC;Hénin J;Lelièvre T;Pohorille A;Chipot C
• 通讯作者: Chipot C

Parametrization of macrolide antibiotics using the force field toolkit.

• DOI: 10.1002/jcc.24043
• 发表时间: 2015-10-15
• 期刊: Journal of computational chemistry
• 影响因子: 3
• 作者: Pavlova A;Gumbart JC
• 通讯作者: Gumbart JC

The mechanism of the amidases: mutating the glutamate adjacent to the catalytic triad inactivates the enzyme due to substrate mispositioning.

酰胺酶的机制：使催化三联体附近的谷氨酸发生突变，由于底物错位而使酶失活。

• DOI: 10.1074/jbc.m113.503284
• 发表时间: 2013
• 期刊: The Journal of biological chemistry
• 作者: Weber,BrandonW;Kimani,SerahW;Varsani,Arvind;Cowan,DonaldA;Hunter,Roger;Venter,GerhardA;Gumbart,JamesC;Sewell,BTrevor
• 通讯作者: Sewell,BTrevor