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Unwinding Induced Melting of Double-Stranded DNA Studied by Free Energy Simulations
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2017-11-19 00:00:00 , DOI: 10.1021/acs.jpcb.7b07701 Korbinian Liebl 1 , Martin Zacharias 1
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2017-11-19 00:00:00 , DOI: 10.1021/acs.jpcb.7b07701 Korbinian Liebl 1 , Martin Zacharias 1
Affiliation
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DNA unwinding plays a major role in many biological processes, such as replication, transcription, and repair. It can lead to local melting and strand separation and can serve as a key mechanism to promote access to the separate strands of a double-stranded DNA. While DNA unwinding has been investigated extensively by DNA cyclization and single-molecule studies on a length-scale of kilo base pairs, it is neither fully understood at the base pair level nor at the level of molecular interactions. By employing a torque acting on the termini of DNA oligonucleotides during molecular dynamics free energy simulations, we locally unwind the central part of a DNA beyond an elastic (harmonic) regime. The simulations reproduce experimental results on the twist elasticity in the harmonic regime (characterized by a mostly quadratic free energy change with respect to changes in twist) and a deformation up to 7° was found as a limit of the harmonic response. Beyond this limit the free energy increase per twist change dropped dramatically coupled to local base pair disruptions and significant deformation of the nucleic acid backbone structure. Restriction of the DNA bending flexibility resulted in a stiffer harmonic response and an earlier onset of the anharmonic response. Whereas local melting with a complete disruption of base pairing and flipping of nucleotides was observed in case of an AT rich central segment strong backbone changes and changes in the stacking arrangements were observed in case of a GC rich segment. Unrestrained MD simulations starting from locally melted DNA reformed regular B-DNA after 50–300 ns simulation time. The simulations may have important implications for understanding DNA recognition processes coupled with significant structural alterations.
中文翻译：
自由能模拟研究双链DNA的解链诱导解链
DNA展开在许多生物学过程（例如复制，转录和修复）中起着重要作用。它可以导致局部解链和链分离，并且可以充当促进接近双链DNA的分离链的关键机制。尽管DNA解旋已通过DNA环化和单分子研究在千碱基对的长度范围内进行了广泛研究，但在碱基对水平或分子相互作用水平上都尚未完全了解。通过在分子动力学自由能模拟过程中施加作用于DNA寡核苷酸末端的扭矩，我们将DNA的中心部分局部展开到弹性（谐波）范围之外。该模拟重现了关于谐波状态下扭转弹性的实验结果（其特征在于，相对于扭转变化，二次自由能的变化大多为二次方），并且发现直至7°的变形是谐波响应的极限。超过该极限，每扭转变化的自由能增加急剧下降，这与局部碱基对破坏和核酸骨架结构的显着变形有关。DNA弯曲柔韧性的限制导致更强的谐波响应和更早的非谐响应的开始。而在富含AT的中央片段的情况下，观察到局部融解，碱基配对和核苷酸的翻转被完全破坏，在富含GC的片段的情况下，观察到了强烈的主链变化和堆积排列的变化。在50–300 ns的模拟时间后，从局部融化的DNA开始的不受约束的MD模拟会重整规则的B-DNA。这些模拟对于理解DNA识别过程以及重大的结构改变可能具有重要的意义。
更新日期：2017-11-20
中文翻译：
自由能模拟研究双链DNA的解链诱导解链
DNA展开在许多生物学过程（例如复制，转录和修复）中起着重要作用。它可以导致局部解链和链分离，并且可以充当促进接近双链DNA的分离链的关键机制。尽管DNA解旋已通过DNA环化和单分子研究在千碱基对的长度范围内进行了广泛研究，但在碱基对水平或分子相互作用水平上都尚未完全了解。通过在分子动力学自由能模拟过程中施加作用于DNA寡核苷酸末端的扭矩，我们将DNA的中心部分局部展开到弹性（谐波）范围之外。该模拟重现了关于谐波状态下扭转弹性的实验结果（其特征在于，相对于扭转变化，二次自由能的变化大多为二次方），并且发现直至7°的变形是谐波响应的极限。超过该极限，每扭转变化的自由能增加急剧下降，这与局部碱基对破坏和核酸骨架结构的显着变形有关。DNA弯曲柔韧性的限制导致更强的谐波响应和更早的非谐响应的开始。而在富含AT的中央片段的情况下，观察到局部融解，碱基配对和核苷酸的翻转被完全破坏，在富含GC的片段的情况下，观察到了强烈的主链变化和堆积排列的变化。在50–300 ns的模拟时间后，从局部融化的DNA开始的不受约束的MD模拟会重整规则的B-DNA。这些模拟对于理解DNA识别过程以及重大的结构改变可能具有重要的意义。
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