Detection of persistent organic pollutants binding modes with androgen receptor ligand binding domain by docking and molecular dynamics.

Background: Persistent organic pollutants (POPs) are persistent in the environment after release from industrial compounds, combustion productions or pesticides. The exposure of POPs has been related to various reproductive disturbances, such as reduced semen quality, testicular cancer, and imbalanced sex ratio. Among POPs, dichlorodiphenyldichloroethylene (4,4'-DDE) and polychlorinated biphenyls (PCBs) are the most widespread and well-studied compounds.

Identification of functionally key residues in AMPA receptor with a thermodynamic method.

AMPA receptor mediates the fast excitatory synaptic transmission in the central nervous system, and it is activated by the binding of glutamate that results in the opening of the transmembrane ion channel. In the present work, the thermodynamic method developed by our group was improved and then applied to identify the functionally key residues that regulate the glutamate-binding affinity of AMPA receptor. In our method, the key residues are identified as those whose perturbation largely changes the ligand binding free energy of the protein.

Identification of key residues for protein conformational transition using elastic network model.

Proteins usually undergo conformational transitions between structurally disparate states to fulfill their functions. The large-scale allosteric conformational transitions are believed to involve some key residues that mediate the conformational movements between different regions of the protein. In the present work, a thermodynamic method based on the elastic network model is proposed to predict the key residues involved in protein conformational transitions.

Insight into the inhibitory mechanism and binding mode between D77 and HIV-1 integrase by molecular modeling methods.

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.

An analysis of the influence of protein intrinsic dynamical properties on its thermal unfolding behavior.

The influence of the protein topology-encoded dynamical properties on its thermal unfolding motions was studied in the present work. The intrinsic dynamics of protein topology was obtained by the anisotropic network model (ANM). The ANM has been largely used to investigate protein collective functional motions, but it is not well elucidated if this model can also reveal the preferred large-scale motions during protein unfolding.

A holistic molecular docking approach for predicting protein-protein complex structure.

A holistic protein-protein molecular docking approach, HoDock, was established, composed of such steps as binding site prediction, initial complex structure sampling, refined complex structure sampling, structure clustering, scoring and final structure selection. This article explains the detailed steps and applications for CAPRI Target 39. The CAPRI result showed that three predicted binding site residues, A191HIS, B512ARG and B531ARG, were correct, and there were five submitted structures with a high fraction of correct receptor-ligand interface residues, indicating that this docking approach may improve prediction accuracy for protein-protein complex structures.

Development of a high-throughput assay for the HIV-1 integrase disintegration reaction.

Both HIV-1 integrase (IN) and the central catalytic domain of IN (IN-CCD) catalyze the disintegration reaction in vitro. In this study, IN and IN-CCD proteins were expressed and purified, and a high-throughput format enzyme-linked immunosorbent assay (ELISA) was developed for the disintegration reaction. IN exhibited a marked preference for Mn(2+) over Mg(2+) as the divalent cation cofactor in disintegration.

Role of electrostatic interactions for the stability and folding behavior of cold shock protein.

The impacts of three charged-residue-involved mutations, E46A, R3E, and R3E/L66E, on the thermostability and folding behavior of the cold shock protein from the themophile Bacillus caldolyticus (Bc-Csp) were investigated by using a modified Gō-like model, in which the nonspecific electrostatic interactions of charged residues were taken into account. Our simulation results show that the wild-type Bc-Csp and its three mutants are all two-sate folders, which is consistent with the experimental observations. It is found that these three mutations all lead to a decrease of protein thermodynamical stability, and the effect of R3E mutation is the strongest.

Study on the binding mode of the integrase with DNA via steered molecular dynamics simulation.

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the lifecycle of this virus and also an important target for the study of anti-HIV drugs. In the current work, a model for the active site of IN and viral DNA was built by combining experimental data with the results of steered molecular dynamics simulation. The model was then taken into a series automatic molecular docking calculations with two groups of inhibitors.

Study on the inhibitory mechanism and binding mode of the hydroxycoumarin compound NSC158393 to HIV-1 integrase by molecular modeling.

Human immunodeficiency virus type 1 integrase (IN) is an essential enzyme in the life cycle of this virus and also an important target for the study of anti-HIV drugs. In this work, the binding modes of the wild type IN core domain and the two mutants, that is, W132G and C130S, with the 4-hydroxycoumarin compound NSC158393 were evaluated by using the "relaxed complex" molecular docking approach combined with molecular dynamics (MD) simulations. Based on the monomer MD simulations, both of the two substitutions affect not only the stability of the 128-136 peptides, but also the flexibility of the functional 140s loop.

Molecular dynamics simulations of the bacterial periplasmic heme binding proteins ShuT and PhuT.

ShuT and PhuT are two periplasmic heme binding proteins that shuttle heme between the outer and inner membranes of the Gram-negative bacteria. Periplasmic binding proteins (PBPs) generally exhibit considerable conformational changes during the ligand binding process, whereas ShuT and PhuT belong to a class of PBPs that do not show such behavior based on their apo and holo crystal structures. By employing a series of molecular dynamic simulations on the ShuT and the PhuT, the dynamics and functions of the two PBPs were investigated.

Evolving model of amino acid networks.

The three-dimensional structure of a protein can be treated as a complex network composed of amino acids, and the network properties can help us to understand the relationship between structure and function. Since the amino acid network of a protein is formed in the process of protein folding, it is difficult for general network models to explain its evolving mechanism. Based on the perspective of protein folding, we propose an evolving model for amino acid networks.

Three-dimensional QSAR analyses of 1,3,4-trisubstituted pyrrolidine-based CCR5 receptor inhibitors.

In this study, a series of 1,3,4-trisubstituted pyrrolidine-based CCR5 receptor inhibitors were taken as our target with the method of the three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses in order to investigate the interactions between CCR5 receptor and their inhibitors. For a comparison, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were, respectively, used to build predictive models, which were generated from a training set consisting of 72 selected molecules, derived from literatures. Two alignment rules, including rigid body rms (root mean square) fit and field fit, were performed in the superimposition of inhibitors structures.

Study on the mechanism of the BtuF periplasmic-binding protein for vitamin B12.

BtuF is the periplasmic binding protein (PBP) that binds vitamin B(12) and delivers it to the periplasmic surface of the ABC transporter BtuCD. PBPs generally exhibit considerable conformational changes during ligand binding process, however, BtuF belongs to a subclass of PBPs that, doesn't show such behavior on the basis of the crystal structures. Employing steered molecular dynamics on the B(12)-bound BtuF, we investigated the energetics and mechanism of BtuF.

Amino acid network and its scoring application in protein-protein docking.

Protein-protein complex, composed of hydrophobic and hydrophilic residues, can be divided into hydrophobic and hydrophilic amino acid network structures respectively. In this paper, we are interested in analyzing these two different types of networks and find that these networks are of small-world properties. Due to the characteristic complementarity of the complex interfaces, protein-protein docking can be viewed as a particular network rewiring.

Protein unfolding behavior studied by elastic network model.

Experimental and theoretical studies have showed that the native-state topology conceals a wealth of information about protein folding/unfolding. In this study, a method based on the Gaussian network model (GNM) is developed to study some properties of protein unfolding and explore the role of topology in protein unfolding process. The GNM has been successful in predicting atomic fluctuations around an energy minimum.

A novel high-throughput format assay for HIV-1 integrase strand transfer reaction using magnetic beads.

Aim: To develop a novel high-throughput format assay to monitor the integrase (IN) strand transfer (ST) reaction in vitro and apply it to a reaction character study and the identification of antiviral drugs.

Methods: The donor DNA duplex, with a sequence identical to the U5 end of HIV-1 long terminal repeats, is labeled at its 5' end with biotin (BIO). The target DNA duplex is labeled at its 3' end with digoxin (DIG).

Prediction of PK-specific phosphorylation site based on information entropy.

Phosphorylation is a crucial way to control the activity of proteins in many eukaryotic organisms in vivo. Experimental methods to determine phosphorylation sites in substrates are usually restricted by the in vitro condition of enzymes and very intensive in time and labor. Although some in silico methods and web servers have been introduced for automatic detection of phosphorylation sites, sophisticated methods are still in urgent demand to further improve prediction performances.

Study on the molecular mechanism of inhibiting HIV-1 integrase by EBR28 peptide via molecular modeling approach.

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the HIV-1 lifecycle which aids the integration of viral DNA into the host chromosome. Recently synthesized 12-mer peptide EBR28, which can strongly bind to IN, is one of the most potential small peptide leading compounds inhibiting IN binding with viral DNA. However, the binding mode between EBR28 peptide with HIV-1 IN and the inhibition mechanism remain uncertain.

A filter enhanced sampling and combinatorial scoring study for protein docking in CAPRI.

Protein-protein docking is usually exploited with a two-step strategy, i.e., conformational sampling and decoy scoring.

Construction and application of the weighted amino acid network based on energy.

A method is proposed to construct the weighted amino acid network. The weight of the link is based on the contact energy between residues. For the 197 proteins with low homology, the "small-world" property was studied based on this method.

Complex-type-dependent scoring functions in protein-protein docking.

A major challenge in the field of protein-protein docking is to discriminate between the many wrong and few near-native conformations, i.e. scoring.

High-throughput real-time assay based on molecular beacons for HIV-1 integrase 3'-processing reaction.

Aim: To develop a high-throughput real-time assay based on molecular beacons to monitor the integrase 3'-processing reaction in vitro and apply it to inhibitor screening.

Methods: The recombinant human immunodeficiency virus (HIV)-1 integrase (IN) is incubated with a 38 mer oligonucleotide substrate, a sequence identical to the U5 end of HIV-1 long terminal repeats (LTR). Based on the fluorescence properties of molecular beacons, the substrate is designed to form a stem-loop structure labeled with a fluorophore at the 5' end and a quencher at the 3' end.

Prediction of the binding model of HIV-1 gp41 with small molecule inhibitors.

Despite the synthetic peptides inhibit HIV-1 entry; its application of this peptide therapy may be limited due to the high cost of the peptide production and lack of its oral availability. Thus, it is necessary to identify the small molecule inhibitors reacting with the same or overlapping target sites on gp41 recognizing the antiviral peptides. In this work, a small inhibitor (TP1) is docked into the hydrophobic grooves of gp41 by using AutoDock software, resulting in five alternative energetically favorable models.

Analysis of domain movements in glutamine-binding protein with simple models.

In this work, the mechanism of domain movements of glutamine-binding protein (GlnBP), especially the influence of the ligand on GlnBP dynamic behavior is investigated with the aid of a Gaussian network model (GNM) and an anisotropy elastic network model. The results show that the "open-closed" transition mainly appears as the large movement of the small domain, especially the top region including two alpha-helices and two beta-strands. The slowest mode of each three forms of GlnBP--ligand-free open, ligand-bound closed, and ligand-free closed GlnBP--shows that the open-closed motion of the two domains has a common hinge axis centered on Lys-87 and Gln-183.