Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90095.
Proc Natl Acad Sci U S A. 2024 Sep 10;121(37):e2322155121. doi: 10.1073/pnas.2322155121. Epub 2024 Sep 3.
Utilizing molecular dynamics and free energy perturbation, we examine the relative binding affinity of several covalent polycyclic aromatic hydrocarbon - DNA (PAH-DNA) adducts at the central adenine of NRAS codon-61, a mutational hotspot implicated in cancer risk. Several PAHs classified by the International Agency for Research on Cancer as probable, possible, or unclassifiable as to carcinogenicity are found to have greater binding affinity than the known carcinogen, benzo[a]pyrene (B[a]P). van der Waals interactions between the intercalated PAH and neighboring nucleobases, and minimal disruption of the DNA duplex drive increases in binding affinity. PAH-DNA adducts may be repaired by global genomic nucleotide excision repair (GG-NER), hence we also compute relative free energies of complexation of PAH-DNA adducts with RAD4-RAD23 (the yeast ortholog of human XPC-RAD23) which constitutes the recognition step in GG-NER. PAH-DNA adducts exhibiting the greatest DNA binding affinity also exhibit the least RAD4-RAD23 complexation affinity and are thus predicted to resist the GG-NER machinery, contributing to their genotoxic potential. In particular, the fjord region PAHs dibenzo[a,l]pyrene, benzo[g]chrysene, and benzo[c]phenanthrene are found to have greater binding affinity while having weaker RAD4-RAD23 complexation affinity than their respective bay region analogs B[a]P, chrysene, and phenanthrene. We also find that the bay region PAHs dibenzo[a,j]anthracene, dibenzo[a,c]anthracene, and dibenzo[a,h]anthracene exhibit greater binding affinity and weaker RAD4-RAD23 complexation affinity than B[a]P. Thus, the study of PAH genotoxicity likely needs to be substantially broadened, with implications for public policy and the health sciences. This approach can be broadly applied to assess factors contributing to the genotoxicity of other unclassified compounds.
利用分子动力学和自由能微扰，我们研究了几种共价多环芳烃-DNA（PAH-DNA）加合物在 NRAS 密码子 61 中中央腺嘌呤的相对结合亲和力，该位点是癌症风险中涉及的突变热点。国际癌症研究机构将几种多环芳烃归类为可能、可能或无法归类为致癌性的物质，我们发现它们比已知的致癌物质苯并[a]芘（B[a]P）具有更高的结合亲和力。嵌入的 PAH 与相邻核碱基之间的范德华相互作用以及 DNA 双链的最小破坏导致结合亲和力的增加。PAH-DNA 加合物可以通过全局基因组核苷酸切除修复（GG-NER）进行修复，因此我们还计算了 PAH-DNA 加合物与 RAD4-RAD23（人类 XPC-RAD23 的酵母同源物）的配合物的相对自由能，RAD4-RAD23 构成 GG-NER 的识别步骤。表现出最大 DNA 结合亲和力的 PAH-DNA 加合物也表现出最弱的 RAD4-RAD23 配合亲和力，因此预计它们会抵抗 GG-NER 机制，从而增加它们的遗传毒性潜力。特别是，发现 fjord 区域的多环芳烃二苯并[a,l]芘、苯并[g]屈和苯并[c]菲比它们各自的海湾区域类似物 B[a]P、屈和菲具有更大的结合亲和力，而 RAD4-RAD23 配合亲和力较弱。我们还发现海湾区域的多环芳烃二苯并[a,j]蒽、二苯并[a,c]蒽和二苯并[a,h]蒽比 B[a]P 具有更大的结合亲和力和较弱的 RAD4-RAD23 配合亲和力。因此，PAH 遗传毒性的研究可能需要大大扩展，这对公共政策和健康科学有影响。这种方法可以广泛应用于评估导致其他未分类化合物遗传毒性的因素。
