Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas 77005, USA.
J Chem Phys. 2011 Apr 28;134(16):165103. doi: 10.1063/1.3568145.
A coarse-grained lattice model of DNA oligonucleotides is proposed to investigate the general mechanisms by which single-stranded oligonucleotides hybridize to their complementary strands in solution. The model, based on a high-coordination cubic lattice, is simple enough to allow the direct simulation of DNA solutions, yet capturing how the fundamental thermodynamic processes are microscopically encoded in the nucleobase sequences. Physically relevant interactions are considered explicitly, such as interchain excluded volume, anisotropic base-pairing and base-stacking, and single-stranded bending rigidity. The model is studied in detail by a specially adapted Monte Carlo simulation method, based on parallel tempering and biased trials, which is designed to overcome the entropic and enthalpic barriers associated with the sampling of hybridization events of multiple single-stranded chains in solution. This methodology addresses both the configurational complexity of bringing together two complementary strands in a favorable orientation (entropic barrier) and the energetic penalty of breaking apart multiple associated bases in a double-stranded state (enthalpic barrier). For strands with sequences restricted to nonstaggering association and homogeneous pairing and stacking energies, base-pairing is found to dominate the hybridization over the translational and conformational entropy. For strands with sequence-dependent pairing corresponding to that of DNA, the complex dependence of the model's thermal stability on concentration, sequence, and degree of complementarity is shown to be qualitatively and quantitatively consistent both with experiment and with the predictions of statistical mechanical models.
提出了一种粗粒化的 DNA 寡核苷酸格子模型，以研究单链寡核苷酸在溶液中与其互补链杂交的一般机制。该模型基于高配位立方格子，简单到足以直接模拟 DNA 溶液，但同时捕捉到基本热力学过程如何在核碱基序列中微观编码。明确考虑了物理相关的相互作用，如链间排斥体积、各向异性碱基配对和碱基堆积以及单链弯曲刚性。通过一种特殊的基于平行回火和有偏试验的蒙特卡罗模拟方法对该模型进行了详细研究，该方法旨在克服与溶液中单链采样相关的熵和焓障碍。这种方法解决了将两条互补链以有利取向聚集在一起的构象复杂性（熵障碍）以及在双链状态下分离多个相关碱基的能量代价（焓障碍）。对于序列限制为非交错聚集和均匀配对和堆积能量的链，碱基配对在杂交过程中主导着平移和构象熵。对于与 DNA 对应的序列相关配对的链，模型的热稳定性对浓度、序列和互补程度的复杂依赖性被证明在定性和定量上都与实验和统计力学模型的预测一致。
