Study on dietary intake, risk assessment, and molecular toxicity mechanism of benzo[α]pyrene in college students in China Bashu area.

As an extremely strong polycyclic aromatic hydrocarbon carcinogen, benzo[α]pyrene (BaP) is often produced during food processing at high temperatures. Recently, food safety, as well as toxicity mechanism and risk assessment of BaP, has received extensive attention. We first constructed the database of BaP pollution concentration in Chinese daily food with over 104 data items; collected dietary intake data using online survey; then assessed dietary exposure risk; and finally revealed the possible toxicity mechanism through four comparative molecular dynamics (MD) simulations. The statistical results showed that the concentration of BaP in olive oil was the highest, followed by that in fried meat products. The margins of exposure and incremental lifetime cancer risk both indicated that the dietary exposure to BaP of the participants was generally safe, but there were still some people with certain carcinogenic risks. Specifically, the health risk of the core district population was higher than that of the noncore district in Bashu area, and the female postgraduate group was higher than the male group with bachelor degree or below. From MD trajectories, BaP binding does not affect the global motion of individual nucleic acid sequences, but local weak noncovalent interactions changed greatly; it also weakens molecular interactions of nucleic acid with Bacillus stearothermophilus DNA polymerase I large fragment (BF), and significantly changes the cavity structure of recognition interface. This work not only reveals the possible toxicity mechanism of BaP, but also provides theoretical guidance for the subsequent optimization of food safety standards and reference of rational diet.

Concepts and Application of DNA Origami and DNA Self-Assembly: A Systematic Review.

With the arrival of the post-Moore Era, the development of traditional silicon-based computers has reached the limit, and it is urgent to develop new computing technology to meet the needs of science and life. DNA computing has become an essential branch and research hotspot of new computer technology because of its powerful parallel computing capability and excellent data storage capability. Due to good biocompatibility and programmability properties, DNA molecules have been widely used to construct novel self-assembled structures. In this review, DNA origami is briefly introduced firstly. Then, the applications of DNA self-assembly in material physics, biogenetics, medicine, and other fields are described in detail, which will aid the development of DNA computational model in the future.

Classification and Design of HIV-1 Integrase Inhibitors Based on Machine Learning.

A key enzyme in human immunodeficiency virus type 1 (HIV-1) life cycle, integrase (IN) aids the integration of viral DNA into the host DNA, which has become an ideal target for the development of anti-HIV drugs. A total of 1785 potential HIV-1 IN inhibitors were collected from the databases of ChEMBL, Binding Database, DrugBank, and PubMed, as well as from 40 references. The database was divided into the training set and test set by random sampling. By exploring the correlation between molecular descriptors and inhibitory activity, it is found that the classification and specific activity data of inhibitors can be more accurately predicted by the combination of molecular descriptors and molecular fingerprints. The calculation of molecular fingerprint descriptor provides the additional substructure information to improve the prediction ability. Based on the training set, two machine learning methods, the recursive partition (RP) and naive Bayes (NB) models, were used to build the classifiers of HIV-1 IN inhibitors. Through the test set verification, the RP technique accurately predicted 82.5% inhibitors and 86.3% noninhibitors. The NB model predicted 88.3% inhibitors and 87.2% noninhibitors with correlation coefficient of 85.2%. The results show that the prediction performance of NB model is slightly better than that of RP, and the key molecular segments are also obtained. Additionally, CoMFA and CoMSIA models with good activity prediction ability both were constructed by exploring the structure-activity relationship, which is helpful for the design and optimization of HIV-1 IN inhibitors.

Specifically Targeting Mtb Cell-Wall and TMM Transporter: The Development of MmpL3 Inhibitors.

Tuberculosis (TB) remains a serious threat to whole human health. In particular, the drug resistance of Mycobacterium tuberculosis (Mtb) has become a huge challenge in clinical medicine, and it is extremely urgent to develop effective inhibitors with novel structures and mechanisms. Belonging to the Resistance, Nodulation and Division (RND) superfamily, Mycobacterial membrane proteins Large 3 (MmpL3) is mainly responsible for transporting mycolic acid outside cell membrane to form cell wall, and plays critical roles in iron acquisition which is vital to the survival of Mtb. As a potential Mtb target in recent years, its inhibitor research has attracted wide attention. A series of inhibitors (such as SQ109, AU1235, BM212, etc.) through experimental screening have been reported in succession, especially SQ109 has entered the clinical stage. In this paper, the structural biology information of target MmpL3 was summarized, and the structure-activity relationship (SAR) of inhibitors reported in recent years and their inhibitory mechanism both were reviewed, aiming to provide help for the rational design of MmpL3 inhibitors in the future.

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

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.