碱基对在DNA双螺旋链上分离的自由能计算（英文）

Free Energy Calculation for Base Pair Dissociation in a DNA Duplex

DNA是大部分生物包括病毒的基因载体。DNA双螺旋链通过A=T和G≡C两种碱基对编码实现对遗传信息的存储。碱基对中的相互作用对DNA双螺旋链的稳定性起到重要作用,直接关系到基因的复制和转录。当前研究中,我们构建了四组不同结构的DNA双螺旋链,进行了总共4.3μs的分子动力学模拟。通过伞形取样技术计算了DNA双螺旋链中碱基对分离的自由能曲线,并从分子尺度细节和相互作用能对自由能曲线进行解析。在碱基对G≡C的自由能曲线(PMF-PGC)上观察到三个峰,通过监测氢键数目的变化发现分别对应于G≡C三个氢键的断裂;而在A=T的自由能曲线(PMF-PAT)上只出现一个峰,说明A=T的两个氢键在分离过程中几乎同时断裂。PMF-PGC的总能垒比PMF-PAT高,主要是因为G≡C比A=T多一个氢键,更稳定。两条曲线的后段自由能仍然升高,而此时碱基对的氢键已断裂,这是DNA链骨架刚性所导致。我们还研究了碱基对稳定性受相邻碱基对的影响,发现邻近G≡C碱基对会增强A=T的稳定性,C≡G会削弱A=T的稳定性,T=A对A=T的影响较小。

DNA is the main genetic material for living organisms including many viruses. DNA duplex, coded with A=T and G≡C base pairs, is well suited for biological information storage. The interactions between two bases in a base pair contribute to the stability of DNA duplex, and are further related to gene replication and transcription. In this study, we use all-atom Molecular dynamics（MD） simulations combined with Umbrella sampling（US） method to determine the free energy profiles and explore the molecular details for base pair dissociations. Four groups of DNA duplexes with different sequences have been constructed and a total of 4.3μs MD simulations have been carried out. In the potential of mean force（PMF） profile for G≡C base pair dissociation（denoted as PMF-PGC）, we observed three peaks, which correspond to the three moments G≡C base pair loses its three hydrogen bonds respectively. Differently, A=T base pair loses its two hydrogen bonds within a very short time. As a result, only one hydrogen bond rupture peak was observed in its PMF curve（denoted as PMF-PAT）. Compared with PMF-PAT, the overall free energy barrier in PMF-PGC is higher, which is due to the better stability of G≡C than A=T. In the latter sections of both PMFs, free energies are still increasing, which is mainly resulted from the rigidity of DNA duplex backbone. We have also investigated the impact of neighboring base pairs on the stability of middle one. It is found that neighboring G≡C base pairsincrease the stability of A=T base pair while neighboring C≡G base pairs reduce the stability of A=T base pair.Additionally, neighboring T=A base pairs have little influence on the stability of A=T base pair.