Erie D A, Suri A K, Breslauer K J, Jones R A, Olson W K
Department of Chemistry, Rutgers, State University of New Jersey, New Brunswick 08903.
Biochemistry. 1993 Jan 19;32(2):436-54. doi: 10.1021/bi00053a008.
A computational procedure for generating conformations of DNA hairpin loop structures from a broad range of low-energy starting states is described. The starting point of the modeling is the distribution of oligonucleotide chain conformations obtained from Monte Carlo simulations of feasible dinucleotide steps. Structures which meet the spatial criteria for hairpin loop formation are selected from the distributions and subsequently minimized using all-atom molecular mechanics. Both d(CTnG) and d(CAnG) oligomers, where n = 3, 4, or 5, are modeled. These sequences are chosen because of the large number of published NMR and thermodynamic studies on DNA hairpins containing thymine or adenine residues. The minimized three-dimensional hairpin loop structures are compared with one another as well as analyzed in terms of available experimental data. The computational approach provides the first detailed analysis of DNA hairpin loop structure in terms of a multistate conformational model. Investigation of the minimized conformations reveals several interesting structural features. First, hairpin loops of the same sequence adopt several distinctly different conformations, as opposed to minor variants of the same equilibrium structure, that could potentially interconvert in solution. Second, in contrast to double-helical nucleic acids, the hairpin loop models exhibit hydrophobic and hydrophilic surfaces. The different disposition of hydrophobic groups in loops versus duplexes could modulate both protein-nucleic acid interactions and nucleic acid self-associations. Third, perpendicular aromatic interactions of loop residues are observed in many of the computed hairpins. This sort of interaction might be important in the stabilization of non-hydrogen-bonded nucleic acid secondary and tertiary structures. The predicted structural features in the models help, in addition, to account for the unusual thermodynamic properties of DNA hairpin loops. Comparison of the theoretically-generated NOEs in different structures further reveals that very different molecular structures and interactions can, in principle, produce the same NOEs. The multistate description suggested by this observation differs from the conventional interpretation of DNA solution structure in terms of the fluctuations about a single preferred chain conformation. There is not necessarily only one set of closely related structures consistent with the observed data.
本文描述了一种计算程序，用于从广泛的低能量起始状态生成DNA发夹环结构的构象。建模的起点是通过对可行二核苷酸步进行蒙特卡罗模拟获得的寡核苷酸链构象分布。从这些分布中选择符合发夹环形成空间标准的结构，随后使用全原子分子力学进行最小化处理。对n = 3、4或5的d(CTnG)和d(CAnG)寡聚物进行了建模。选择这些序列是因为已发表了大量关于含有胸腺嘧啶或腺嘌呤残基的DNA发夹的核磁共振（NMR）和热力学研究。将最小化后的三维发夹环结构相互比较，并根据现有的实验数据进行分析。该计算方法首次根据多状态构象模型对DNA发夹环结构进行了详细分析。对最小化构象的研究揭示了几个有趣的结构特征。首先，相同序列的发夹环采用几种明显不同的构象，而不是同一平衡结构的微小变体，这些构象在溶液中可能会相互转化。其次，与双螺旋核酸不同，发夹环模型呈现出疏水和亲水表面。环与双链体中疏水基团的不同排列可能会调节蛋白质 - 核酸相互作用以及核酸的自缔合。第三，在许多计算得到的发夹中观察到环残基的垂直芳香相互作用。这种相互作用可能对非氢键结合的核酸二级和三级结构的稳定很重要。此外，模型中预测的结构特征有助于解释DNA发夹环异常的热力学性质。不同结构中理论生成的核Overhauser效应（NOE）的比较进一步表明，原则上非常不同的分子结构和相互作用可以产生相同的NOE。这一观察结果所暗示的多状态描述不同于传统上对DNA溶液结构的解释，即围绕单一优选链构象的波动。不一定只有一组与观测数据一致的密切相关结构。
