Simulating Biomolecular Machines: ATP Powered DNA Translocation in Helicases

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。链切割是许多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）移位并诱导dsDNA/ssDNA接合处的DNA碱基对的解链。在双链体解旋之后，通过将RNA碱基与现在分离的DNA碱基配对来进行转录等过程。沿着DNA的沿着移位和DNA碱基对的解旋都是由ATP水解提供动力的。虽然解旋酶沿着沿着DNA的移位机制已经得到了极大的关注，但是对ATP水解、碱基对切割和沿着沿着DNA的移位之间的耦合的充分理解是缺失的。 解旋酶运动沿着DNA的反应性和多尺度性质使得它在计算上是一个困难的问题。在这个方向上的重大进展，可以与耦合和修改两种模拟方法。ATP水解反应可以明确地处理与使用修改的多态经验价键（MS-EVB）方法。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。第一个是诱导碱基对解链，第二个是沿着沿着DNA骨架移动。这种多尺度行为与长时间尺度的过程相结合，对标准的原子或粗粒度（CG）分子动力学（MD）提出了挑战。多尺度粗粒化（MS-CG）技术存在于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尺度。结合MS-EVB和MS-CG技术将允许解旋酶蛋白的水解驱动运动的第一个直接模拟。

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.