Bioactive conformational generation of small molecules: A comparative analysis between force-field and multiple empirical criteria based methods

<p>Abstract</p> <p>Background</p> <p>Conformational sampling for small molecules plays an essential role in drug discovery research pipeline. Based on multi-objective evolution algorithm (MOEA), we have developed a conformational generation method called Cyndi in the previous study. In this work, in addition to Tripos force field in the previous version, Cyndi was updated by incorporation of MMFF94 force field to assess the conformational energy more rationally. With two force fields against a larger dataset of 742 bioactive conformations of small ligands extracted from PDB, a comparative analysis was performed between pure force field based method (FFBM) and multiple empirical criteria based method (MECBM) hybrided with different force fields.</p> <p>Results</p> <p>Our analysis reveals that incorporating multiple empirical rules can significantly improve the accuracy of conformational generation. MECBM, which takes both empirical and force field criteria as the objective functions, can reproduce about 54% (within 1Å RMSD) of the bioactive conformations in the 742-molecule testset, much higher than that of pure force field method (FFBM, about 37%). On the other hand, MECBM achieved a more complete and efficient sampling of the conformational space because the average size of unique conformations ensemble per molecule is about 6 times larger than that of FFBM, while the time scale for conformational generation is nearly the same as FFBM. Furthermore, as a complementary comparison study between the methods with and without empirical biases, we also tested the performance of the three conformational generation methods in MacroModel in combination with different force fields. Compared with the methods in MacroModel, MECBM is more competitive in retrieving the bioactive conformations in light of accuracy but has much lower computational cost.</p> <p>Conclusions</p> <p>By incorporating different energy terms with several empirical criteria, the MECBM method can produce more reasonable conformational ensemble with high accuracy but approximately the same computational cost in comparison with FFBM method. Our analysis also reveals that the performance of conformational generation is irrelevant to the types of force field adopted in characterization of conformational accessibility. Moreover, post energy minimization is not necessary and may even undermine the diversity of conformational ensemble. All the results guide us to explore more empirical criteria like geometric restraints during the conformational process, which may improve the performance of conformational generation in combination with energetic accessibility, regardless of force field types adopted.</p

Deletion of 1.8-kb mRNA of Marek's disease virus decreases its replication ability but not oncogenicity

<p>Abstract</p> <p>Background</p> <p>The 1.8-kb mRNA was reported as one of the oncogenesis-related genes of Marek's disease virus (MDV). In this study, the bacterial artificial chromosome (BAC) clone of a MDV field strain GX0101 was used as the platform to generate mutant MDV to examine the functional roles of 1.8-kb mRNA.</p> <p>Results</p> <p>Based on the BAC clone of GX0101, the 1.8-kb mRNA deletion mutant GX0101Δ(A+C) was constructed. The present experiments indicated that GX0101Δ(A+C) retained a low level of oncogenicity, and it showed a decreased replication capacity in vitro and in vivo when compared with its parent virus, GX0101. Further studies in vitro demonstrated that deletion of 1.8-kb mRNA significantly decreased the transcriptional activity of the bi-directional promoter between 1.8-kb mRNA and pp38 genes of MDV.</p> <p>Conclusion</p> <p>These results suggested that the 1.8-kb mRNA did not directly influence the oncogenesis but related to the replication ability of MDV.</p

Linear and nonlinear optical properties of some organoxenon derivatives

We employ a series of state-of-the-art computational techniques to study the effect of inserting one or more Xe atoms in HC2H and HC4H, on the linear and nonlinear optical (L&NLO) properties of the resulting compounds. It has been found that the inserted Xe has a great effect on the L&NLO properties of the organoxenon derivatives. We analyze the bonding in HXeC2H, and the change of the electronic structure, which is induced by inserting Xe, in order to rationalize the observed extraordinary L&NLO properties. The derivatives, which are of interest in this work, have been synthesized in a Xe matrix. Thus the effect of the local field (LF), due to the Xe environment, on the properties of HXeC2H, has also been computed. It has been found that the LF effect on some properties is significant. The calculations have been performed by employing a hierarchy of basis sets and the techniques MP2 and CCSD(T) for taking into account correlation. For the interpretation of the results we have employed the complete active space valence bond and CASSCF/CASPT2 [email protected]

Linear and nonlinear optical properties of a series of Ni-dithiolene derivatives

Some linear and nonlinear optical (NLO) properties of Ni(SCH)4 and several of its derivatives have been computed by employing a series of basis sets and a hierarchy of methods (e.g., HF, DFT, coupled cluster, and multiconfigurational techniques). The electronic structure of Ni(SCH)4 has been also analyzed by using CASSCF/CASPT2, ab initio valence bond, and DFT methods. In particular we discuss how the diradicaloid character (DC) of Ni(SCH)4 significantly affects its NLO properties. The quasidegeneracy of the two lowest-energy singlet states 1 mathg and 1 math1u, the clear DC nature of the former, and the very large number of low-lying states enhance the NLO properties values. These particular features are used to interpret the NLO properties of Ni(SCH)4. The DC of the considered derivatives has been estimated and correlated with the NLO properties. CASVB computations have shown that the structures with Ni(II) are the dominant ones, while those with Ni(0) and Ni(IV) have negligible weight. The weights of the four diradical structures were discussed in connection with the weight of the structures, where all the electrons are paired. Comparative discussion of the properties of Ni(SCH)4 with those of tetrathia fulvalene demonstrates the very large effect of Ni on the properties of the Ni-dithiolene derivatives. A similar remarkable effect on the NLO properties is produced by one or two methyl or C3S groups. The considered Ni-dithiolene derivatives have exceptionally large NLO properties. This feature in connection with their other physical properties makes them ideal candidates for photonic [email protected]

GTWS-MLrec: global terrestrial water storage reconstruction by machine learning from 1940 to present

Terrestrial water storage (TWS) includes all forms of water stored on and below the land surface, and is a key determinant of global water and energy budgets. However, TWS data from measurements by the Gravity Recovery and Climate Experiment (GRACE) satellite mission are only available from 2002, limiting global and regional understanding of the long-term trends and variabilities in the terrestrial water cycle under climate change. This study presents long-term (i.e., 1940–2022) and relatively high-resolution (i.e., 0.25∘) monthly time series of TWS anomalies over the global land surface. The reconstruction is achieved by using a set of machine learning models with a large number of predictors, including climatic and hydrological variables, land use/land cover data, and vegetation indicators (e.g., leaf area index). The outcome, machine-learning-reconstructed TWS estimates (i.e., GTWS-MLrec), fits well with the GRACE/GRACE-FO measurements, showing high correlation coefficients and low biases in the GRACE era. We also evaluate GTWS-MLrec with other independent products such as the land–ocean mass budget, atmospheric and terrestrial water budget in 341 large river basins, and streamflow measurements at 10 168 gauges. The results show that our proposed GTWS-MLrec performs overall as well as, or is more reliable than, previous TWS datasets. Moreover, our reconstructions successfully reproduce the consequences of climate variability such as strong El Niño events. The GTWS-MLrec dataset consists of three reconstructions based on (a) mascons of the Jet Propulsion Laboratory of the California Institute of Technology, the Center for Space Research at the University of Texas at Austin, and the Goddard Space Flight Center of NASA; (b) three detrended and de-seasonalized reconstructions; and (c) six global average TWS series over land areas, both with and without Greenland and Antarctica. Along with its extensive attributes, GTWS_MLrec can support a wide range of geoscience applications such as better understanding the global water budget, constraining and evaluating hydrological models, climate-carbon coupling, and water resources management. GTWS-MLrec is available on Zenodo through https://doi.org/10.5281/zenodo.10040927 (Yin, 2023)

Phylogeography and demographic history of the cyprinid fish Barbodes semifasciolatus: implications for the history of landform changes in south mainland China, Hainan and Taiwan

Hainan Island and Taiwan Island are adjacent to the southern margin of mainland China and Vietnam. During glacial periods, global sea levels dropped, allowing that the land bridges connected the continental island and mainland, connecting rivers and providing dispersal opportunities that shaped the origin and diversification of freshwater fishes. Barbodes semifasciolatus is distributed in various water systems of Vietnam, Hainan, Taiwan, and southern mainland China and is restricted to the southern region of the Min River. Our study aimed to evaluate the genetic diversity and phylogeography of B. semifasciolatus using the mtDNA cyt b gene (1,141 bp). A total of 107 haplotypes were identified from 395 specimens in 23 populations, and high haplotype diversity (1.000) and low nucleotide diversity (0.0134) were detected. Mitochondrial phylogenetic analysis and haplotype network analyses revealed three major lineages according to geographical distribution. Lineage A was mainly distributed in Hainan Island, Vietnam and the southern region of the Pearl River in mainland China. Lineage B was distributed only in southeastern Hainan Island. Lineage C was distributed in the coastal rivers of mainland China and Taiwan. We suggest that the river in the Guangdong region is a colonization route in South Taiwan and that the populations distributed in the Pearl River region moved southward to Hainan Island and Vietnam based on the network and Bayesian binary MCMC (BBM) analysis. Our demographic history results indicated that the populations of B. semifasciolatus experienced a bottleneck event following a recent population expansion (DECINC model) supported by ABC analysis. We suggest that sea-level changes exerted pronounced effects on the demography of B. semifasciolatus on the continental island and in the mainland during the late Pleistocene glacial cycles

TELEX HEBDOMADAIRE NR 95 DU 17.09.82 DESTINE A L'ENSEMBLE DES DELEGATIONS EXTERIEURES ET BUREAUX DE PRESS ET D'INFORMATION INDEPENDANTS DANS LES PAYS TIERS = WEEKLY MEMO NO. 95 FOR 17.09.82 TO FOREIGN DELEGATIONS AND PRESS BUREAUS OF THIRD COUNTRIES

<p>High-performance liquid chromatography (HPLC) results of (A) commercial surfactin sample, and (B) our extract surfactin of <i>B</i>. <i>subtilis</i> HH2 in LB medium. There were three main peaks (Peak A-C) of the extract and the surfactin standard in the same location.</p