利用多層級分子模擬對雙股螺旋核酸力學性質的探討

Abstract

雙股螺旋核酸在最新的生物科技與生物工程技術中扮演著重要的角色，而最重要的兩種雙股螺旋核酸分別為雙股DNA與雙股RNA。在化學結構上，DNA比RNA少一個羥基，而這樣一個微小的差別，卻讓兩種分子擁有非常不同的結構型態與力學特性，最終導致兩者在生物體內負責著不同的功能。在此篇研究中，我們利用分子模擬與多層級粗礫化模型來探討雙股DNA、雙股RNA與混和系統的結構特性與力學關聯。首先，無論雙股DNA的起始結構是A-form或B-form，皆會收斂到類B-form的結構。對於雙股RNA，若起始結構是A-form，會保持非常穩定的A-form。然而，若雙股RNA的起始結構是B-form，在模擬的過程中會出現許多的鹼基破壞或二級結構，這也顯示了RNA中的羥基會使雙股RNA的位能面比雙股DNA的位能面還崎嶇。對於混和系統，RNA股會保持穩定的A-form，而DNA股也會偏好A-form結構。此外，多層級的計算方法能量化這三個系統中重要的作用力對於力學性質的貢獻。從此方法，我們得知雙股RNA在骨架與核糖上的力學關聯比雙股DNA還強，而雙股DNA鹼基的力學關聯比雙股RNA強，混和系統中RNA股與DNA股的力學關聯則改變了原本存在於雙股DNA與雙股RNA的特性。最後，我們發現雙股RNA在鹼基上的力學關聯對於序列有明顯的特異性。

Nucleic acids duplexes are an important class of biomolecules and a set of widely used tools in biotechnology and bioengineering. A key question for this system is how does the subtle difference in chemical structure between DNA and RNA cause diverse structure and mechanical properties in the duplexes of nucleic acids and hence a wide range of biological functions and activities. In this work, all-atom molecular dynamics simulations and multiscale coarse grained modeling were conducted to resolve the structures and mechanical couplings in 21-bp duplexes of dsDNA, dsRNA, and hybrid strands. It was found that dsDNA converged to B-form like structures starting from different initial structures, and dsRNA strongly preferred to the A-form structure in the simulation starting from an A-form conformation. In a simulation of dsRNA starting from the B-form structure, though, base-opening events and noncanonical structures were sampled, indicating that the more rugged potential energy surface with the presence of the 2'-hydroxyl group. For the hybrid systems, the hybrid RNA strand retained A-form structure, and the DNA strand was shifted to A-form like. Furthermore, the multiscale computational framework developed here allowed quantitive comparison of the strengths of mechanical couplings for the different interactions in a molecular system as well as across different systems. It was thus established that dsRNA has significantly higher force constant values for mechanical couplings in backbone and sugar puckering than those of dsDNA. For nucleobase interactions of hydrogen bonding and stacking, on the other hand, dsDNA exhibited stronger mechanical couplings. As a DNA and a RNA strand hybridized into a duplex, mechanical couplings drifted from their behaviors in the homo-duplex in a specific manners. A key finding was that the sequence dependences of nucleobase interactions were particularly pronounced in the RNA strand of hybrid systems.