Langley D R
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Wallingford, CT 06492-7660, USA.
J Biomol Struct Dyn. 1998 Dec;16(3):487-509. doi: 10.1080/07391102.1998.10508265.
Molecular dynamic (MD) simulations using the BMS nucleic acid force field produce environment and sequence dependent DNA conformations that closely mimic experimentally derived structures. The parameters were initially developed to reproduce the potential energy surface, as defined by quantum mechanics, for a set of small molecules that can be used as the building blocks for nucleic acid macromolecules (dimethyl phosphate, cyclopentane, tetrahydrofuran, etc.). Then the dihedral parameters were fine tuned using a series of condensed phase MD simulations of DNA and RNA (in zero added salt, 4M NaCl, and 75% ethanol solutions). In the tuning process the free energy surface for each dihedral was derived from the MD ensemble and fitted to the conformational distributions and populations observed in 87 A- and B-DNA x-ray and 17 B-DNA NMR structures. Over 41 nanoseconds of MD simulations are presented which demonstrate that the force field is capable of producing stable trajectories, in the correct environments, of A-DNA, double stranded A-form RNA, B-DNA, Z-DNA, and a netropsin-DNA complex that closely reproduce the experimentally determined and/or canonical DNA conformations. Frequently the MD averaged structure is closer to the experimentally determined structure than to the canonical DNA conformation. MD simulations of A- to B- and B- to A-DNA transitions are also shown. A-DNA simulations in a low salt environment cleanly convert into the B-DNA conformation and converge into the RMS space sampled by a low salt simulation of the same sequence starting from B-DNA. In MD simulations using the BMS force field the B-form of d(GGGCCC)2 in a 75% ethanol solution converts into the A-form. Using the same methodology, parameters, and conditions the A-form of d(AAATTT)2 correctly converts into the B-DNA conformation. These studies demonstrate that the force field is capable of reproducing both environment and sequence dependent DNA structures. The 41 nanoseconds (nsec) of MD simulations presented in this paper paint a global picture which suggests that the DNA structures observed in low salt solutions are largely due to the favorable internal energy brought about by the nearly uniform screening of the DNA electrostatics. While the conformations sampled in high salt or mixed solvent environments occur from selective and asymmetric screening of the phosphate groups and DNA grooves, respectively, brought about by sequence induced ion and solvent packing.
使用BMS核酸力场进行的分子动力学（MD）模拟产生了依赖于环境和序列的DNA构象，这些构象与实验得出的结构非常相似。这些参数最初是为了重现由量子力学定义的一组小分子的势能面而开发的，这些小分子可作为核酸大分子的构建模块（磷酸二甲酯、环戊烷、四氢呋喃等）。然后，通过对DNA和RNA进行一系列凝聚相MD模拟（在零添加盐、4M NaCl和75%乙醇溶液中）对二面角参数进行了微调。在调整过程中，每个二面角的自由能面是从MD系综中推导出来的，并与在87个A-DNA和B-DNA X射线结构以及17个B-DNA NMR结构中观察到的构象分布和群体进行拟合。本文展示了超过41纳秒的MD模拟，结果表明该力场能够在正确的环境中产生稳定的轨迹，模拟A-DNA、双链A-form RNA、B-DNA、Z-DNA以及一个纺锤菌素-DNA复合物，这些模拟结果与实验确定的和/或经典的DNA构象非常接近。通常，MD平均结构比经典DNA构象更接近实验确定的结构。本文还展示了A-DNA到B-DNA以及B-DNA到A-DNA转变的MD模拟。在低盐环境中对A-DNA的模拟能够顺利转变为B-DNA构象，并收敛到从B-DNA开始的相同序列的低盐模拟所采样的RMS空间中。在使用BMS力场的MD模拟中，75%乙醇溶液中的d(GGGCCC)2的B-form会转变为A-form。使用相同的方法、参数和条件，d(AAATTT)2的A-form能够正确转变为B-DNA构象。这些研究表明，该力场能够重现依赖于环境和序列的DNA结构。本文呈现的41纳秒MD模拟描绘了一幅全局图景，表明在低盐溶液中观察到的DNA结构很大程度上归因于DNA静电几乎均匀屏蔽所带来的有利内能。而在高盐或混合溶剂环境中采样的构象分别是由序列诱导的离子和溶剂堆积对磷酸基团和DNA凹槽进行选择性和不对称屏蔽所导致的。
