Simulating Biomolecular Machines: ATP Powered DNA Translocation in Helicases

模拟生物分子机器：解旋酶中 ATP 驱动的 DNA 易位

• 批准号: 8468936
• 负责人: Martin McCullagh
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468936
• 关键词: ATP Hydrolysis; Algorithms; Amino Acids; Attention; Base Pairing; Behavior; Binding; Biological; Cell physiology; Cereals; Computing Methodologies; Coupling; Energy Transfer; Environment; Event; Freedom; Genetic Transcription; Glean; Hereditary Disease; Hydrolysis; Individual; Investigation; Length; Malignant Neoplasms; Mechanics; Methodology; Methods; Modeling; Modification; Molecular; Molecular Machines; Molecular Motors; Monitor; Motion; Motor; Nature; Pharmaceutical Preparations; Process; Proteins; Protons; RNA; Reaction; Resolution; Simulate; Single-Stranded DNA; Site; Structure; System; Techniques; Time; Vertebral column; Work; aqueous; base; biological systems; chemical reaction; design; ds-DNA; helicase; melting; molecular dynamics; monomer; novel; repaired; research study; simulation

DESCRIPTION (provided by applicant): Helicase proteins induce duplex melting of double stranded DNA (dsDNA). Strand cleavage is a pivotal step in numerous DNA related cellular processes including transcription, replication and repair. Most helicases translocate along single stranded DNA (ssDNA) and induce melting of DNA base pairs at the dsDNA/ssDNA junction. Processes such as transcription are done subsequent to the unwinding of the duplex by pairing RNA bases to the now separated DNA base. Both translocation along DNA and unwinding of DNA base pairs are powered by ATP hydrolysis. While significant attention has been given to the mechanism of helicase translocation along DNA, a full understanding of the coupling between ATP hydrolysis, base pair cleavage and translocation along DNA is missing. The reactive and multi-scale nature of helicase motion along DNA makes it a difficult problem to approach computationally. Significant strides in this direction can be made with the coupling and modification of two simulation methods. The ATP hydrolysis reaction can be treated explicitly with the use of a modified multi-state empirical valence bond (MS-EVB) method. MS-EVB is a reactive force field developed to treat proton transfer in aqueous environments. The underlying method, however, is general and can be adapted to treat numerous chemical reactions. The energy from ATP hydrolysis is converted into mechanical work for two purposes by the helicase protein. The first is to induce base pair melting and the second is to move along the DNA backbone. This multi-scale behavior combined with the long time scale of the processes present a challenge for standard atomistic or coarse-grained (CG) molecular dynamics (MD). Multi-scale coarse graining (MS-CG) techniques exist to systematically coarse-grain a system using the underlying atomistic forces. This allows for seamless integration of multiple length scales in a single MD simulation. Combining MS-EVB and MS-CG techniques will allow for the first direct simulation of hydrolysis driven motion of helicase proteins.

描述（由申请人提供）：解旋蛋白诱导双链DNA（DSDNA）的双链熔化。链裂解是许多与DNA相关的细胞过程中的关键步骤，包括转录，复制和修复。大多数解旋酶沿单个链DNA（ssDNA）转移，并在DSDNA/SSDNA连接处诱导DNA碱基对熔化。通过将RNA碱基配对与现在分离的DNA碱基，进行了转录之类的过程。沿着DNA的易位和DNA碱基对的放松均由ATP水解提供动力。尽管对沿DNA的解旋酶易位的机理有了很大的关注，但缺少对ATP水解，基对裂解和沿DNA易位之间的耦合的完全理解。 沿DNA的解旋酶运动的反应性和多尺度性质使得很难进行计算接近。可以通过两种仿真方法的耦合和修改来朝这个方向上的显着步伐。 ATP水解反应可以通过使用改良的多态经验价键（MS-EVB）方法明确处理。 MS-EVB是一个反应力场，用于处理水性环境中的质子转移。但是，基本方法是一般的，可以适应用于治疗众多化学反应。 ATP水解的能量通过解旋酶蛋白进行了两个目的转化为机械工作。第一个是诱导碱基对熔化，第二个是沿着DNA主链移动。这种多尺度行为与过程的长期尺度相结合，对标准原子或粗粒（CG）分子动力学（MD）提出了挑战。使用潜在的原子力在系统上有粗粒的系统，存在多尺度的粗透明（MS-CG）技术。这允许在单个MD模拟中无缝整合多个长度尺度。将MS-EVB和MS-CG技术组合起来将允许对解旋酶蛋白的水解驱动运动进行首次直接模拟。