A combinatorial scoring function for protein-RNA docking.

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.

Allosteric transitions of ATP-binding cassette transporter MsbA studied by the adaptive anisotropic network model.

The transporter MsbA is a kind of multidrug resistance ATP-binding cassette transporter that can transport lipid A, lipopolysaccharides, and some amphipathic drugs from the cytoplasmic to the periplasmic side of the inner membrane. In this work, we explored the allosteric pathway of MsbA from the inward- to outward-facing states during the substrate transport process with the adaptive anisotropic network model. The results suggest that the allosteric transitions proceed in a coupled way.

Allosteric transitions of the maltose transporter studied by an elastic network model.

The maltose transporter from Escherichia coli is one of the ATP-binding cassette (ABC) transporters that utilize the energy from ATP hydrolysis to translocate substrates across cellular membranes. Until 2011, three crystal structures have been determined for maltose transporter at different states in the process of transportation. Here, based on these crystal structures, the allosteric pathway from the resting state (inward-facing) to the catalytic intermediate state (outward-facing) is studied by applying an adaptive anisotropic network model.

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.

The current status and challenges in the development of fusion inhibitors as therapeutics for HIV-1 infection.

HIV-1 membrane fusion as a part of the process of viral entry in the target cells is facilitated by gp41 and gp120, which are encoded by Env gene of HIV-1. Based on the structure and the mechanism researches, new treatment options targeting HIV-1 entry process have been proposed. Enfuvirtide, which mimics amino acid sequences of viral envelope glycoprotein gp41, is the first HIV-1 fusion inhibitor approved by FDA.

The interactions and recognition of cyclic peptide mimetics of Tat with HIV-1 TAR RNA: a molecular dynamics simulation study.

The interaction of HIV-1 trans-activator protein Tat with its cognate trans-activation response element (TAR) RNA is critical for viral transcription and replication. Therefore, it has long been considered as an attractive target for the development of antiviral compounds. Recently, the conformationally constrained cyclic peptide mimetics of Tat have been tested to be a promising family of lead peptides.

[Effect of pre-electroacupuncture at "Zusanli" (ST 36) on DA and 5-HT contents and their ratio in hypothalamus and striatum in exercise rats].

Objective: To observe anti-fatigue effect and mechanisms of pre-electroacupuncture (EA) at "Zusanli" (ST 36) in rats undergoing acute treadmill running.

Methods: Fifty male SD rats were randomly divided into three groups: a quiet group (group Q, n = 10), a model group (group M, n = 20) and an EA preconditioning group (group EAP, n = 20). After adaptation for undergoing treadmill running, all the rats in group M and group EAP were trained on acute treadmill running.

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.

A new residue-nucleotide propensity potential with structural information considered for discriminating protein-RNA docking decoys.

Understanding the key factors that influence the preferences of residue-nucleotide interactions in specific protein-RNA interactions has remained a research focus. We propose an effective approach to derive residue-nucleotide propensity potentials through considering both the types of residues and nucleotides, and secondary structure information of proteins and RNAs from the currently largest nonredundant and nonribosomal protein-RNA interaction database. To test the validity of the potentials, we used them to select near-native structures from protein-RNA docking poses.

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.

Computer-aided design, synthesis, and biological activity evaluation of potent fusion inhibitors targeting HIV-1 gp41.

This discovered and optimized several novel HIV-1 fusion inhibitors and further evaluated the inhibitory activities of these compounds in vitro. Here, we have reported the computer-aided design, synthesis, and biological evaluation of a series of small molecule fusion inhibitors targeting HIV-1 gp41. Based on the structure of inhibitor (NB2), we carried out de novo design and screened out a series of novel structure molecules by using Leapfrog and Autodock programs.

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.

Design, synthesis and anti-HIV integrase evaluation of N-(5-chloro-8-hydroxy-2-styrylquinolin-7-yl)benzenesulfonamide derivatives.

Styrylquinoline derivatives are demonstrated to be HIV-1 integrase inhibitors. On the basis of our previous CoMFA analysis of a series of styrylquinoline derivatives, N-[(2-substituted-styryl)-5-chloro-8-hydroxyquinolin-7-yl]-benzenesulfonamide derivatives were designed and synthesized,and their possible HIV IN inhibitory activity was evaluated.

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.

[Effects of transcutaneous electric acupoint stimulation on plasma SOD and MDA in rats with sports fatigue].

Objective: To observe the effect of transcutaneous electric acupoint stimulation (TEAS) on plasma superoxide dismutase (SOD) and malondialdehyde (MDA) in rats with sports fatigue so as to explore its mechanisms in resisting exercise-induced fatigue.

Methods: Twenty-seven male adult SD rats were randomly divided into control group (n 9), model group (n=9) and TEAS group (n=9). Sports fatigue model was established by using treadmill method, i.

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.