Zhong Jin

Binding Free Energy Estimation for Protein-Ligand Complex Based on MM-PBSA with Various Partial Charge Models

An accurate estimation of binding free energy between protein and ligand, is one of the most important issues in the drug discovery process. However, it is an arduous and hard process to obtain accurate energy, especially the experimentally relevant free energies for protein-ligand in solution, including a proper treatment of the long-range electrostatics and solvation effects that are involved in optimization of atomic net charges and so on. In this study, the impacts of the various atomic net charge models were considered, and their effects on binding free energy profiles also were investigated. The methods were tested on: the 30 structurally diverse ligands of diverse protein complexes, the 14 structurally diverse ligands of the protein kinase B (PKB) and the 10 structurally diverse ligands of the cyclin-dependent kinases 2 (CDK2) with measured affinities. The tested charges were calculated based on AM1 (Austin Method, version 1) - BCC (bond charge correction), MNDO (modified neglect of diatomic differential overlay), PM5 (Parameterisation Model, version 5), MUL (Mulliken), CM2 (Charge Model 2), CM3 (Charge Model 3), RESP (restrained electrostatic potential) and QM/MM (quantum mechanics/molecular mechanics) models. Our findings showed that the MNDO charge model was best propitious for PKB system and QM/MM for CDK2, whereas none of any given models was suited for the diverse ligands of diverse protein complexes. The trends of MM-PBSA binding free energies using all charge models were in good accord with experimental results for CDK2 but not for PKB in most cases. Considering the above results, particular attention should be paid to the ligand-charge and maybe protein-charge during the estimation of accurate binding free energies in drug design.

GridMol: a grid application for molecular modeling and visualization.

In this paper we present GridMol, an extensible tool for building a high performance computational chemistry platform in the grid environment. GridMol provides computational chemists one-stop service for molecular modeling, scientific computing and molecular information visualization. GridMol is not only a visualization and modeling tool but also simplifies control of remote Grid software that can access high performance computing resources. GridMol has been successfully integrated into China National Grid, the most powerful Chinese Grid Computing platform. In Section “Grid computing” of this paper, a computing example is given to show the availability and efficiency of GridMol. GridMol is coded using Java and Java3D for portability and cross-platform compatibility (Windows, Linux, MacOS X and UNIX). GridMol can run not only as a stand-alone application, but also as an applet through web browsers. In this paper, we will present the techniques for molecular visualization, molecular modeling and grid computing. GridMol is available free of charge under the GNU Public License (GPL) from our website: http://www.sccas.cn/~syh/GridMol/index.html Contact: syh@sccas.cn

VCGDB: a dynamic genome database of the Chinese population

BackgroundThe data released by the 1000 Genomes Project contain an increasing number of genome sequences from different nations and populations with a large number of genetic variations. As a result, the focus of human genome studies is changing from single and static to complex and dynamic. The currently available human reference genome (GRCh37) is based on sequencing data from 13 anonymous Caucasian volunteers, which might limit the scope of genomics, transcriptomics, epigenetics, and genome wide association studies.DescriptionWe used the massive amount of sequencing data published by the 1000 Genomes Project Consortium to construct the Virtual Chinese Genome Database (VCGDB), a dynamic genome database of the Chinese population based on the whole genome sequencing data of 194 individuals. VCGDB provides dynamic genomic information, which contains 35 million single nucleotide variations (SNVs), 0.5 million insertions/deletions (indels), and 29 million rare variations, together with genomic annotation information. VCGDB also provides a highly interactive user-friendly virtual Chinese genome browser (VCGBrowser) with functions like seamless zooming and real-time searching. In addition, we have established three population-specific consensus Chinese reference genomes that are compatible with mainstream alignment software.ConclusionsVCGDB offers a feasible strategy for processing big data to keep pace with the biological data explosion by providing a robust resource for genomics studies; in particular, studies aimed at finding regions of the genome associated with diseases.

The Challenge to the Rule of Homology Modeling: Folding Mechanism Study of Protein GA and GB with High Sequence Identity but Different Native Structures

As one of the most valuable methods for drug design, homology modeling shows that protein structures are more conserved than protein sequences, that is, the proteins with high sequence identity have high structural similarity, but protein pairs G(A)88/G(B)88 and G(A)95/G(B)95 prove the opposite. The pairs G(A)88 and G(B)88 shares the 88% sequence identity, but display different structures, and the pair G(A)95 and G(B)95 with 95% sequence identity yet presents different structures. The research on these proteins provides an opportunity of complementary study. In the process of protein folding, at which stage the protein final structure was determined and which residues were important for folding to a given structure were still unknown. Here we used OPLS all-atom force field for molecular dynamics simulations to study the unfolding of G(A)88, G(B)88, G(A)95 and G(B)95 at high temperatures, and used the process of protein unfolding to reverse the process of protein folding. G(B)88 and G(B)95 folded to the α+β structure, but G(A)88 and G(A)95 folded to the all-α-helix structure. In the process of G(A)88 and G(A)95 folding, the helices folded earlier than the formation of tertiary interactions. In the process of folding to G(B)88 and G(B)95, the α-helix formed earlier. We showed that early along the folding pathway, the final protein structure was confirmed, and very small differences between protein sequences determined the protein structure.

HSA: A Heuristic Splice Alignment Tool

BackgroundRNA-Seq methodology is a revolutionary transcriptomics sequencing technology, which is the representative of Next generation Sequencing (NGS). With the high throughput sequencing of RNA-Seq, we can acquire much more information like differential expression and novel splice variants from deep sequence analysis and data mining. But the short read length brings a great challenge to alignment, especially when the reads span two or more exons.MethodsA two steps heuristic splice alignment tool is generated in this investigation. First, map raw reads to reference with unspliced aligner - BWA; second, split initial unmapped reads into three equal short reads (seeds), align each seed to the reference, filter hits, search possible split position of read and extend hits to a complete match.ResultsCompare with other splice alignment tools like SOAPsplice and Tophat2, HSA has a better performance in call rate and efficiency, but its results do not as accurate as the other software to some extent.ConclusionsHSA is an effective spliced aligner of RNA-Seq reads mapping, which is available at https://github.com/vlcc/HSA.

PGAweb: A Web Server for Bacterial Pan-Genome Analysis

An astronomical increase in microbial genome data in recent years has led to strong demand for bioinformatic tools for pan-genome analysis within and across species. Here, we present PGAweb, a user-friendly, web-based tool for bacterial pan-genome analysis, which is composed of two main pan-genome analysis modules, PGAP and PGAP-X. PGAweb provides key interactive and customizable functions that include orthologous clustering, pan-genome profiling, sequence variation and evolution analysis, and functional classification. PGAweb presents features of genomic structural dynamics and sequence diversity with different visualization methods that are helpful for intuitively understanding the dynamics and evolution of bacterial genomes. PGAweb has an intuitive interface with one-click setting of parameters and is freely available at http://PGAweb.vlcc.cn/.

Three-dimensional numerical simulation of viscoelastic phase separation under shear: the roles of bulk and shear relaxation moduli

The morphological, dynamic and rheological characteristics in the viscoelastic phase separation (VPS) of sheared polymer solutions are investigated by three-dimensional (3D) numerical simulations of viscoelastic model. The simulations are accelerated by graphic process unit (GPU) to break through the limitation of computation power. Firstly, the morphological and dynamic characteristics of VPS under shear are presented by comparing with those in classic phase separation (CPS). The results show that the phase inversion and phase shrink take place in VPS under shear. Then, the roles of bulk and shear relaxation moduli in VPS are investigated in details. The bulk relaxation modulus slows down the phase separation process under shear, but not affects the dynamic path of VPS. The dynamic path can be divided into three stages: freezing stage, growth stage and stable stage. The second overshoot phenomenon in the shear stress is observed, and explained by the breakdown and reform of string structures. The shear modulus affects morphology evolution in the late stage of VPS under shear.

BAsplice: Bi-direction alignment for detecting splice junctions

RNA-Seq is a revolutionary whole transcriptome shotgun sequencing technology performed by high-throughput sequencers, which provide more comprehensive information on differential expression of genes and benefit on novel splice variants identification. RNA-Seq reads is so short that its a great challenge on mapping reads back to the reference effectively, especially when they span two or more exons. To improve the mapping efficiency, we introduce here a bi-direction alignment tool - BAsplice, which use RNA-Seq data to detect splice junctions without any additional information. Compare with another splice junction mapping software, SOAPsplice, BAsplice performs better in call rate and running time, but a little worse in accuracy. BAsplice is a free open-source software written in C language. It is available at https://github.com/vlcc/basplice.