The stereochemical properties of ligands that form covalent adducts with DNA have profound effects on their biochemical functions. Differing absolute configurations of substituents about chiral carbon atoms can lead to strikingly different conformations when such stereoisomeric compounds bind to DNA. The environmental chemical carcinogen, benzo[a]pyrene (BP), provides a remarkable example of such stereochemical effects. Metabolic activation of benzo[a]pyrene leads to a pair of enantiomers, (+)-(7R,8S,9S,10R)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and its (-)-(7S,8R,9R,10S) mirror-image, known as (+)-and (-)-anti-BPDE. Both (+)-and (-)-anti-BPDE react with the amino group of adenine in DNA via trans epoxide opening, yielding a pair of stereochemically distinct trans-anti-benzo[a]pyrenyl adducts, whose possible role in chemical carcinogenesis is of great interest. High-resolution NMR solution studies (Schurter et al.
As part of a comprehensive effort to understand the origins of the variety of structural motifs adopted by (+)- and (-)-cis- and trans-anti-[BP]-N(2)-dG and -N(6)-dA adducts, with the goal of contributing to the elucidation of the structure-function relationship, we present results of our comprehensive computational investigation of the C10R (+)-cis- and C10S (-)-cis-anti-[BP]-N(6)-dA adducts on the nucleoside level. We have surveyed the potential energy surface of these two adducts by varying systematically, at 5 degrees intervals in combination, the three key torsion angle determinants of conformational flexibility (chi, alpha', and beta') in each adduct, creating 373 248 structures, and evaluating each of their energies. This has permitted us to map the entire potential energy surface of each adduct and to delineate the low-energy regions. The energy maps possess a symmetric relationship in the (+)/(-) adduct pair. This symmetry in the maps stems from the mirror image configuration of the benzylic rings in the two adducts, which produces opposite orientations of the BP residues in the C10R and C10S adducts on the nucleoside level. These opposite orientations result from primary steric hindrance between the base and the BP moiety which ensues when a (+) stereoisomer is rotated to the conformation favored by the (-) stereoisomer, and vice versa. Moreover, this steric hindrance manifested on the nucleoside level governs the structure on the duplex DNA level, accounting for observed opposite orientations in high-resolution NMR studies of C10R/C10S adduct pairs.
Protein-RNA docking is still an open question. One of the main challenges is to develop an effective scoring function that can discriminate near-native structures from the incorrect ones. To solve the problem, we have constructed a knowledge-based residue-nucleotide pairwise potential with secondary structure information considered for nonribosomal protein-RNA docking. Here we developed a weighted combined scoring function RpveScore that consists of the pairwise potential and six physics-based energy terms. The weights were optimized using the multiple linear regression method by fitting the scoring function to L_rmsd for the bound docking decoys from Benchmark II. The scoring functions were tested on 35 unbound docking cases. The results show that the scoring function RpveScore including all terms performs best. Also RpveScore was compared with the statistical mechanics-based method derived potential ITScore-PR, and the united atom-based statistical potentials QUASI-RNP and DARS-RNP. The success rate of RpveScore is 71.6% for the top 1000 structures and the number of cases where a near-native structure is ranked in top 30 is 25 out of 35 cases. For 32 systems (91.4%), RpveScore can find the binding mode in top 5 that has no lower than 50% native interface residues on protein and nucleotides on RNA. Additionally, it was found that the long-range electrostatic attractive energy plays an important role in distinguishing near-native structures from the incorrect ones. This work can be helpful for the development of protein-RNA docking methods and for the understanding of protein-RNA interactions. RpveScore program is available to the public at http://life.bjut.edu.cn/kxyj/kycg/2017116/14845362285362368_1.html Proteins 2017; 85:741-752. © 2016 Wiley Periodicals, Inc.
Models for the layout of production lines have been studied in this paper. First, it constructed a model of Multi-row Mix Integer Programming for the Flexible Manufacturing Systems. Secondly, using the genetic algorithms to analyze, it established the effective solutions. Finally, it completed the evaluation of the program. Demonstrating the feasibility and effectiveness method through the case of studies, a new method was given for the layout of large-scale production line.
Integrase is an essential enzyme in the life cycle of Human immunoficiency virus type 1 (HIV-1) and also an important target for designing integrase inhibitors. In this paper, the binding modes between the wild type integrase core domain (ICD) and the W131A mutant ICD with the benzoic acid derivative--D77 were investigated using the molecular docking combined with molecular dynamics (MD) simulations. The result of MD simulations showed that the W131A substitution affected the flexibility of the region 150-167 in both the monomer A and B of the mutant type ICD. In principle, D77 interacted with the residues around the Lens Epithelium-Derived Growth Factor (LEDGF/p75) binding site which is nearby the HIV-1 integrase dimer interface. However, the specific binding modes for D77-wild type integrase and D77-mutant integrase systems are various. According to the binding mode of D77 with the wild type ICD, D77 can effectively intervene with the binding of LEDGF/p75 to integrase due to a steric hindrance effect around the LEDGF/p75 binding site. In addition, we found that D77 might also affect its inhibitory action by reducing the flexibility of the region 150-167 of integrase. Through energy decomposition calculated with the Molecular Mechanics Generalized Born Surface Area approach to estimate the binding affinity, it seems likely that W131 and E170 are indispensable for the ligand binding, as characterized by the largest binding affinity. All the above results are consistent with the experimental data, providing us with some helpful information not only for the understanding of the mechanism of this kind of inhibitor but also for the rational drug design.
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