Molecular modeling of the conformational complexity of (+)-anti-B[a]PDE-adducted DNA using simulated annealing.
Molecular modeling of the conformational complexity of (+)-anti-B[a]PDE-adducted DNA using simulated annealing.
复制标题
使用模拟退火对 ( )-抗 B[a]PDE 加合 DNA 的构象复杂性进行分子建模。
DOI：
10.1093/carcin/18.8.1585
复制
发表时间：
1997
期刊：
影响因子：
4.7
通讯作者：
Loechler,EL
中科院分区：
文献类型：
--
作者：
Kozack,RE;Loechler,EL
苯并[a]芘（B[a]P）是一种强效诱变剂/致癌剂，在代谢后与DNA反应生成相应的（+）-抗-7，8-二醇-9，10-环氧化物[（+）-抗-B [a]PDE]，生成主要加合物（+）-反式-抗-B[a]P-N2-dG。有证据表明，这种加合物负责大多数不同类型的突变（例如G->T，G->A等）。由（+）-抗B [a]PDE诱导，提出了一个单一加合物如何引起许多不同类型突变的问题？一种假设是，不同的突变诱导取决于构象的这种加合物时，绕过DNA复制。如果是真的，那么就必须探索这种加合物的不同合理构象。本文采用模拟退火方法研究双链体DNA中5 '-CGC-3'序列背景下（+）-反式-抗B[a]P-N2-dG的构象，其中B[a]P部分位于小沟中并指向其5 '侧的碱基。选择该构象和序列是因为存在来自NMR约束的结构用于比较。遵循四步程序：将加合物对接在规范B-DNA中，之后使结构经受初始共辄梯度最小化，随后模拟退火和最终共辄梯度最小化。结构的质量和最终能量被评估为六个参数的变化的函数，包括DNA螺旋的长度、初始退火温度（T0）、退火时间（t）、分子动力学时间步长（tau）和另外两个参数。虽然没有一组最佳参数，合理的低能量结构，获得使用值t约40 ps（或更长），T0约750 K和tau约1.0 fs的螺旋长度为7 bp。出现的结构都保留了输入结构的基本特征，是B-DNA样的，小沟中的B[a]P部分指向5 '侧的碱基。然而，在这一大类中，至少有六个结构子类，其中四个具有最低能量成员，相差<约5 kcal/mol。事实上，各种不同的，但相关的结构出现从一个单一的起始结构，因为这个参数集是不同的，这表明，使用一个大的，但可管理的数量的模拟退火运行应考虑在寻找一个队列的相关结构。这一点尤其重要，因为能量大致相同的潜在相关结构的宽度可能确实与不同构象的单一加合物产生不同突变的假设有关。
Benzo[a]pyrene (B[a]P), a potent mutagen/carcinogen, reacts with DNA following metabolism to its corresponding (+)-anti-7,8-diol-9,10-epoxide [(+)-anti-B[a]PDE], giving a major adduct (+)-trans-anti-B[a]P-N2-dG. Evidence suggests that this adduct is responsible for most of the different kinds of mutations (e.g. G-->T, G-->A, etc.) induced by (+)-anti-B[a]PDE, raising the question of how can a single adduct cause many different kinds of mutations? One hypothesis is that different mutations are induced depending upon the conformation of this adduct when bypassed during DNA replication. If true, then it becomes imperative to explore different reasonable conformations for this adduct. Herein a simulated annealing protocol is employed to study the conformation of (+)-trans-anti-B[a]P-N2-dG with the B[a]P moiety in the minor groove and pointing toward the base on its 5'-side in a 5'-CGC-3' sequence context in duplex DNA. This conformation and sequence were chosen because there is a structure derived from NMR constraints for comparison. A four step procedure is followed: the adduct is docked in canonical B-DNA, after which the structure is subjected to an initial conjugate gradient minimization, followed by simulated annealing and a final conjugate gradient minimization. The quality and final energy of structures is assessed as a function of changes in six parameters, including the length of the DNA helix, the initial annealing temperature (T0), the annealing time (t), the molecular dynamics time step (tau) and two other parameters. While there is no single set of optimum parameters, reasonable low energy structures were obtained using the values t approximately 40 ps (or longer), T0 approximately 750 K and tau approximately 1.0 fs with a helix length of 7 bp. The structures that emerge all retain the basic features of the input structure, being B-DNA-like with the B[a]P moiety in the minor groove pointing toward the base on the 5'-side. However, within this broad category there are at least six subclasses of structures, of which four have lowest energy members that differ by < approximately 5 kcal/mol. The fact that a variety of distinct but related structures emerge from a single starting structure as this parameter set is varied suggests that the use of a large but manageable number of simulated annealing runs should be considered in the search for a cohort of related structures. This is especially important given that this breadth of potentially relevant structures of approximately the same energy may indeed be relevant to the hypothesis that different mutations arise from a single adduct in different conformations.