Cheatham T E, Srinivasan J, Case D A, Kollman P A
Laboratory of Biophysical Chemistry, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892-5626, USA.
J Biomol Struct Dyn. 1998 Oct;16(2):265-80. doi: 10.1080/07391102.1998.10508245.
Molecular dynamics simulation in explicit solvent and continuum solvent models are applied to investigate the relative stability of A- and B-form helices for two DNA sequences, dA10-dT10 and dG10-dC10 in three structural forms. One structural form is based on an unrestrained molecular dynamics (MD) trajectory starting from a canonical B-DNA structure, the second is based on a MD trajectory starting in a canonical B-DNA structure with the sugars constrained to be C2'-endo and the third simulation started from a canonical A-DNA structure with the sugars constrained to C3'-endo puckers. For the energetic analysis, structures were taken as snapshots from nanosecond length molecular dynamics simulations computed in a consistent fashion in explicit solvent, applying the particle mesh Ewald method and the Cornell et al. force field. The electrostatic contributions to solvation free energies are computed using both a finite-difference Poisson-Boltzmann model and a pairwise Generalized Born model. The non-electrostatic contributions to the solvation free energies are estimated with a solvent accessible surface area dependent term. To estimate the gas phase component of the relative free energy between the various structures, the mean solute internal energies (determined with the Cornell et al. molecular mechanics potential including all pairwise interactions within the solute) and estimates of the solute entropy (using a harmonic approximation) were used. Consistent with experiment, the polyG-polyC (GC) structures are found to be much more A-phillic than the polyA-polyT (AT) structures, the latter being quite A-phobic. The dominant energy components responsible for this difference comes from the internal and van der Waal energies. A perhaps less appreciated difference between the GC and AT rich sequences is suggested by the calculated salt dependence which demonstrates a significantly enhanced ability to drive GC rich sequences towards an A-form structure compared to AT rich sequences. In addition to being A-phobic, the AT structure also has a noticably larger helical repeat than GC and other mixed sequence duplexes, consistent with experiment. Analysis of the average solvent density from the trajectories shows hydration patterns in qualitative agreement with experiment and previous theoretical treatments.
在显式溶剂模型和连续介质溶剂模型中应用分子动力学模拟，以研究两个DNA序列dA10 - dT10和dG10 - dC10在三种结构形式下A-和B-型螺旋的相对稳定性。一种结构形式基于从经典B-DNA结构开始的无约束分子动力学（MD）轨迹，第二种基于从经典B-DNA结构开始且糖基被约束为C2'-内型的MD轨迹，第三种模拟从经典A-DNA结构开始且糖基被约束为C3'-内型褶皱。对于能量分析，结构是从在显式溶剂中以一致方式计算的纳秒级分子动力学模拟的快照中获取的，应用了粒子网格埃瓦尔德方法和康奈尔等人的力场。使用有限差分泊松-玻尔兹曼模型和成对广义玻恩模型计算静电对溶剂化自由能的贡献。用一个依赖于溶剂可及表面积的项估计非静电对溶剂化自由能的贡献。为了估计各种结构之间相对自由能的气相成分，使用了平均溶质内能（用康奈尔等人的分子力学势确定，包括溶质内的所有成对相互作用）和溶质熵的估计值（使用谐波近似）。与实验一致，发现聚G-聚C（GC）结构比聚A-聚T（AT）结构更倾向于A-型，后者相当排斥A-型。造成这种差异的主要能量成分来自内能和范德华能。计算出的盐依赖性表明，与富含AT的序列相比，富含GC的序列有显著增强的能力驱动其向A-型结构转变，这表明了GC和AT丰富序列之间一个可能较少被认识到的差异。除了排斥A-型外，AT结构的螺旋重复也明显大于GC和其他混合序列双链体，这与实验一致。对轨迹中平均溶剂密度的分析表明，水合模式在定性上与实验和先前的理论处理一致。
