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BP[dG]-induced distortions to DNA polymerase and DNA duplex: A detailed mechanism of BP adducts blocking replication.

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机构： [a]College of Pharmacy and Biological Engineering, Sichuan Industrial Institute of Antibiotics, Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China [b]College of Mathematics and Informatics, South China Agricultural University, Guangzhou, China [c]Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China

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关键词： Benzo[α]pyrene DNA polymerases Molecular dynamics simulation Toxicity Risk management

摘要：

As one of the most widespread environmental pollutants, benzo[α]pyrene is metabolized to diol epoxides and then covalently breaks the initial DNA base pairs, which has been closely related to the occurrence and development of many human cancers. High fidelity DNA polymerases play an extremely important role in maintaining the reliability or fidelity of nucleic acid replication, which is generally blocked by BP adducts. To reveal the blocking mechanism of BP, two comparative molecular dynamics simulations were performed for the thermophilic Bacillus stearothermophilus DNA polymerase I large fragment (BF) complexes with normal and BP-bound DNA duplexes. The results of global conformational changes and molecular interactions show that the association of BP leads to the rearrangement of intramolecular hydrogen bonds, impairing the molecular recognition between the polymerase and the DNA duplex. It is also found that the conformation of DNA duplex is distorted, accompanied by an increase in molecular overall rigidity. In terms of possible blocking mechanisms, the BP moiety perfectly integrates itself into the base-paired environment in a special vertical conformation and occupies the space required for the incoming nucleotide. This work provides useful dynamics and structural information for understanding the toxic effect of BP on DNA replication at atomic level. Copyright © 2020 Elsevier Ltd. All rights reserved.

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出版当年[2020]版：

大类 | 2 区

医学

小类 | 1 区毒理学 2 区食品科技

最新[2023]版：

大类 | 3 区医学

小类 | 3 区食品科技 3 区毒理学

第一作者：

第一作者机构： [a]College of Pharmacy and Biological Engineering, Sichuan Industrial Institute of Antibiotics, Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China

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通讯作者：

通讯机构： [a]College of Pharmacy and Biological Engineering, Sichuan Industrial Institute of Antibiotics, Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China [c]Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China [*1]College of Pharmacy and Bioengineering, Chengdu University, Chengdu, 610106, China. [*2]State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610041, China.

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