GSA-Human: Genome Sequence Archive for Human.

The Genome Sequence Archive for Human (GSA-Human) is a data repository specialized for human genetic related data derived from biomedical researches, and also supports the data collection and management of National Key Research and Development Projects. GSA-Human has a data security management strategy according to the national regulations of human genetic resources. It provides two different models of data access: Open-access and Controlled-access. Open-access data are universally and freely accessible for global researchers, while Controlled-access ensures that data are accessed only by authorized users with the permission of the Data Access Committee (DAC). Till July 2021, GSA-Human has housed more than 5.27 PB of data from 750 datasets.

An online coronavirus analysis platform from the National Genomics Data Center.

Since the first reported severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in December 2019, coronavirus disease 2019 (COVID-19) has become a global pandemic, spreading to more than 200 countries and regions worldwide. With continued research progress and virus detection, SARS-CoV-2 genomes and sequencing data have been reported and accumulated at an unprecedented rate. To meet the need for fast analysis of these genome sequences, the National Genomics Data Center (NGDC) of the China National Center for Bioinformation (CNCB) has established an online coronavirus analysis platform, which includes de novoassembly, BLAST alignment, genome annotation, variant identification, and variant annotation modules. The online analysis platform can be freely accessed at the 2019 Novel Coronavirus Resource (2019nCoVR) (https://bigd.big.ac.cn/ncov/online/tools).

[Database resources of the reference genome and genetic variation maps for the Chinese population].

With the implementation of the international human genome project and 1000 genome project, hundreds of Chinese individual genome sequences have been published. Establishing a high-precision Chinese population reference genome and identifying the unique genome variations are fundamental for future precision medicine research in China. To further meet the needs of scientific management and deep mining on the rapidly growing Chinese genomic data, Beijing Institute of Genomics, Chinese Academy of Sciences, has developed a Virtual Chinese Genome Database (VCGDB, http://bigd.big.ac.cn/vcg/) and Genome Variation Map (GVM, http://bigd.big.ac.cn/gvm/) based on the public whole genome sequencing data, which provides the worldwide services of data retrieval, sharing, downloading and online analysis. This paper presents the brief introduction of characteristics and functions of the two databases, as well as their future development and application prospects, aiming to provide useful information for the promotion and development of the reference genome and genome variation map database in China.

A scenario on the stepwise evolution of the genetic code.

It is believed that in the RNA world the operational (ribozymes) and the informational (riboscripts) RNA molecules were created with only three (adenosine, uridine, and guanosine) and two (adenosine and uridine) nucleosides, respectively, so that the genetic code started uncomplicated. Ribozymes subsequently evolved to be able to cut and paste themselves and riboscripts were acceptive to rigorous editing (adenosine to inosine); the intensive diversification of RNA molecules shaped novel cellular machineries that are capable of polymerizing amino acids-a new type of cellular building materials for life. Initially, the genetic code, encoding seven amino acids, was created only to distinguish purine and pyrimidine; it was later expanded in a stepwise way to encode 12, 15, and 20 amino acids through the relief of guanine from its roles as operational signals and through the recruitment of cytosine. Therefore, the maturation of the genetic code also coincided with (1) the departure of aminoacyl-tRNA synthetases (AARSs) from the primordial translation machinery, (2) the replacement of informational RNA by DNA, and (3) the co-evolution of AARSs and their cognate tRNAs. This model predicts gradual replacements of RNA-made molecular mechanisms, cellular processes by proteins, and informational exploitation by DNA.

Homology modeling and PAPS ligand (cofactor) binding study of bovine phenol sulfotransferase.

In order to understand the mechanisms of ligand binding and the interaction between the ligand and the bovine phenol sulfotransferase, (bSULT1A1, EC 2.8.2.1) a three-dimensional (3D) model of the bSULT1A1 is generated based on the crystal structure of the estrogen sulfotransferase (PDB code 1AQU) by using the InsightII/Homology module. With the aid of the molecular mechanics and molecular dynamics methods, the final refined model is obtained and is further assessed by Profile-3D and ProStat, which show that the refined model is reliable. With this model, a flexible docking study is performed and the results indicate that 3'-phosphoadenosine-5'- phosphosulfate (PAPS) is a more preferred ligand than coenzyme A (CoA), and that His108 forms hydrogen bond with PAPS, which is in good agreement with the experimental results. From these docking studies, we also suggest that Phe255, Phe24 and Tyr169 in bSULT1A1 are three important determinant residues in binding as they have strong van-der-Waals contacts with the ligand. The hydrogen-bonding interactions also play an important role for the stability of the complex. Our results may be helpful for further experimental investigations.

Homology modeling and molecular dynamics study of GSK3/SHAGGY-like kinase.

Although the GSK3/SHAGGY-like kinase is a highly conserved serine/threonine kinase implicated in many signaling pathways in eukaryotes, the lack of knowledge of its three-dimensional (3D) structure has hindered efforts to understand the binding specificities of substrate and catalytic mechanism. To understand the structure-activity relationships, the protein 3D structure was built by using homology modeling based on the known X-ray diffraction structure of Glycogen synthase kinase-3beta (Gsk3beta) and the model structure was further refined using unrestrained molecular dynamics simulations. The research indicates that the general 3D organization of the GSK3/SHAGGY-like kinase is a typical kinase family and comprises an N-terminal domain of beta-sheet and a larger C-terminal domain mainly constituted by alpha-helix. In order to understand the molecular interactions between the natural substrate-ATP and GSK3/SHAGGY-like kinase, a 3D model of the complex ATP-GSK3/SHAGGY-like kinase is developed by molecular docking program, which is helpful to guide the experimental realization and the new mutant designs as well. One important finding is that the identification of the key binding-site residue of Lys69 which plays an important role in the catalysis of GSK3/SHAGGY-like kinase and this is in consistent with experimental observation.

Homology modeling and molecular dynamics studies of a novel C3-like ADP-ribosyltransferase.

The novel C3-like ADP-ribosyltransferase is produced by a Staphylococcus aureus strain that especially ADP-ribosylates RhoE/Rnd3 subtype proteins, and its three-dimensional (3D) structure has not known. In order to understand the catalytic mechanism, the 3D structure of the protein is built by using homology modeling based on the known crystal structure of exoenzyme C3 from Clostridium botulinum (1G24). Then the model structure is further refined by energy minimization and molecular dynamics methods. The putative nicotinamide adenine dinucleotide (NAD(+))-binding pocket of exoenzyme C3(Stau) is determined by Binding-Site Search module. The NAD(+)-enzyme complex is developed by molecular dynamics simulation and the key residues involved in the combination of enzyme binding to the ligand-NAD(+) are determined, which is helpful to guide the experimental realization and the new mutant designs as well. Our results indicated that the key binding-site residues of Arg48, Glu180, Ser138, Asn134, Arg85, and Gln179 play an important role in the catalysis of exoenzyme C3(Stau), which is in consistent with experimental observation.

Theoretical study on the rate constants for the C2H5 + HBr --> C2H6 + Br reaction.

The reaction C(2)H(5) + HBr --> C(2)H(6) + Br has been theoretically studied over the temperature range from 200 to 1400 K. The electronic structure information is calculated at the BHLYP/6-311+G(d,p) and QCISD/6-31+G(d) levels. With the aid of intrinsic reaction coordinate theory, the minimum energy paths (MEPs) are obtained at the both levels, and the energies along the MEP are further refined by performing the single-point calculations at the PMP4(SDTQ)/6-311+G(3df,2p)//BHLYP and QCISD(T)/6-311++G(2df,2pd)//QCISD levels. The calculated ICVT/SCT rate constants are in good agreement with available experimental values, and the calculate results further indicate that the C(2)H(5) + HBr reaction has negative temperature dependence at T < 850 K, but clearly shows positive temperature dependence at T > 850 K. The current work predicts that the kinetic isotope effect for the title reaction is inverse in the temperature range from 200 to 482 K, i.e., k(HBr)/k(DBr) < 1.

Ab initio direct dynamics studies on the reaction of H atom with CH3CH2Cl.

The multiple channel reaction H + CH(3)CH(2)Cl --> products has been studied by the ab initio direct dynamics method. The potential energy surface information is calculated at the MP2/6-311G(d,p) level of theory. The energies along the minimum energy path are further improved by single-point energy calculations at the PMP4(SDTQ)/6-311+G(3df,2p) level of theory. For the reaction, four reaction channels (one chlorine abstraction, one alpha-hydrogen abstraction, and two beta-hydrogen abstractions) have been identified. The rate constants for each reaction channel are calculated by using canonical variational transition state theory incorporating the small-curvature tunneling correction in the temperature range 298-5000 K. The total rate constants, which are calculated from the sum of the individual rate constants, are in good agreement with the experimental data. The calculated temperature dependence of the branching fractions indicates that for the title reaction, H-abstraction reaction is the major reaction channel in the whole temperature range 298-5000 K.

DFT and ab initio direct dynamics studies on the hydrogen abstraction reactions of chlorine atoms with CH(4-n)F(n) (n = 1-3).

A direct dynamics study is carried out for the hydrogen abstraction reactions Cl + CH(4-n)F(n) (n = 1-3) in the temperature range of 200-1,000 K. The minimum energy paths (MEPs) of these reactions are calculated at the BH&H-LYP/6-311G(d,p) level, and the energies along the MEPs are further refined at the QCISD(T)/6-311+G(2df,2p) and QCISD(T)/6-311+G(d,p) (single-point) level. The rate constants obtained by using the improved canonical variational transition state theory incorporating small-curvature tunneling correction (ICVT/SCT) are in good agreement with the available experimental results. It is shown that the vibrational adiabatic potential energy curves for these reactions have two barriers, a situation similar to the analogous reactions CH(3)X+Cl (X=Cl, Br). The theoretical results show that for the title reactions the variational effect should not be neglected over the whole considered temperature range, while the small-curvature tunneling effect is only important in the lower temperature range. The effects of fluorine substitution on the rate of this kind of reactions are also examined.

Direct ab initio dynamics study on the rate constants and kinetic isotope effect for the reactions of H atoms with GeDn(CH3)4-n (n = 1-4).

Direct ab initio dynamic calculations are performed on the reactions of atomic hydrogen with GeD(n)(CH(3))(4-n) (n = 1-4) over the temperature range 200-2000 K at the PMP4SDTQ/6-311 +G(3df,2p)//MP2/6-31 +G(d) (for n = 2-4) and G2//MP2/6-31 +G(d) (for n = 1) levels. The corresponding k(H)/k(D) ratios are then calculated in order to determine the kinetic isotope effect for the four reactions. For the simplest GeD(4) +H reaction, the only one that has available experimental data, the calculated canonical variational transition state theory incorporates small-curvature tunneling correction (CVT/SCT) thermal rate constants, and the k(H)/k(D) values are in good agreement with the experimental values within the experimental temperature range 293-550 K. For the four GeD(n)(CH(3))(4-4) (n = 1-4) reactions, the variational effect is small over the whole temperature range, whereas the small-curvature effect is important in the lower temperature range. Finally, the overall rate constants are fitted to the three-parameter expression over the whole temperature range 200-2000 K as 5.8 x 10(8)T(1.68)exp(-929/T), 1.7 x 10(8)T(1.80)exp(-691/T), 2.58 x 10(8)T(1.71)exp(-706/T), and 1.0 x 10(7)T(2.08)exp(-544/T) cm(3) mol(-1) s(-1) for the n = 4, 3, 2, and 1 reactions. Our work may represent the first theoretical study of the kinetic isotope effect for the H-attack on the G-H bonding.