Simulating Biomolecular Machines: ATP Powered DNA Translocation in Helicases

描述(申请人提供)：解旋酶蛋白诱导双链DNA(DsDNA)的双链熔化。链切割是许多与DNA相关的细胞过程中的关键步骤，包括转录、复制和修复。大多数解旋酶沿着单链DNA(SsDNA)转位，并在dsDNA/ssDNA连接处导致DNA碱基对的融化。在双链解链后，通过将RNA碱基与现在分离的DNA碱基配对来完成转录等过程。沿DNA的移位和DNA碱基对的解离都是由ATP水解酶提供动力的。虽然人们对解旋酶沿DNA转位的机制给予了很大的关注，但对ATP水解酶、碱基对切割和DNA转位之间的耦合还缺乏充分的了解。解旋酶沿DNA运动的反应性和多尺度特性使其成为一个难以计算的问题。通过两种模拟方法的耦合和修改，可以在这一方向上取得重大进展。用改进的多态经验价键(MS-EVB)方法可以显式地处理ATP的水解反应。MS-EVB是一种反应力场，用于处理水环境中的质子转移。然而，基本的方法是通用的，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。第一种是诱导碱基对融化，第二种是沿着DNA骨架移动。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)技术存在使用底层原子力系统地粗粒化系统。这允许在单个MD模拟中无缝集成多个长度标尺。结合MS-EVB和MS-CG技术将允许第一次直接模拟解旋酶蛋白质的水解驱动运动。

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.