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: 8316571
• 负责人: Martin McCullagh
• 金额: $ 4.92万
• 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/8316571
• 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. PUBLIC HEALTH RELEVANCE: Helicases are unique motor proteins involved in DNA replication, transcription and repair. Understanding the mechanism by which helicases translocate along the DNA backbone is pivotal to aiding in the design of targeted anti-cancer and anti-genetic disorder drugs. We propose novel computational methods to study the ATP hydrolysis energy transduction process of two helicase proteins.

描述（由申请人提供）：解旋酶蛋白诱导双链DNA（dsDNA）的双链体解链。链断裂是许多 DNA 相关细胞过程（包括转录、复制和修复）中的关键步骤。大多数解旋酶沿着单链 DNA (ssDNA) 易位并诱导 dsDNA/ssDNA 连接处的 DNA 碱基对解链。双链体解旋后，通过将 RNA 碱基与现在分离的 DNA 碱基配对，完成转录等过程。沿着 DNA 的易位和 DNA 碱基对的解旋都是由 ATP 水解提供动力的。虽然人们对解旋酶沿 DNA 易位的机制给予了极大的关注，但对 ATP 水解、碱基对切割和沿 DNA 易位之间的耦合却缺乏充分的了解。 解旋酶沿着 DNA 运动的反应性和多尺度性质使其成为一个难以通过计算解决的问题。通过两种模拟方法的耦合和修改，可以在这个方向上取得重大进展。 ATP 水解反应可以使用改进的多态经验价键 (MS-EVB) 方法明确处理。 MS-EVB 是一种反作用力场，旨在处理水环境中的质子转移。然而，基本方法是通用的，可以适用于处理许多化学反应。解旋酶蛋白将 ATP 水解产生的能量转化为机械功，用于两个目的。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时间尺度相结合，对标准原子或粗粒度 (CG) 分子动力学 (MD) 提出了挑战。多尺度粗粒化 (MS-CG) 技术可利用底层原子力系统地对系统进行粗粒化。这允许在单个 MD 模拟中无缝集成多个长度尺度。结合 MS-EVB 和 MS-CG 技术将首次直接模拟解旋酶蛋白质的水解驱动运动。 公共卫生相关性：解旋酶是参与 DNA 复制、转录和修复的独特马达蛋白。了解解旋酶沿着 DNA 主链易位的机制对于帮助设计靶向抗癌和抗遗传性疾病药物至关重要。我们提出了新的计算方法来研究两种解旋酶蛋白的 ATP 水解能量转导过程。