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951.
Fangfang Yan Shaolong Zhang Jing Su Qinggang Zhang 《Journal of biomolecular structure & dynamics》2013,31(14):3583-3595
AbstractAdipocyte fatty acid binding protein (A-FABP) is a potential drug target for treatment of diabetes, obesity and atherosclerosis. Molecular dynamics (MD) simulations, principal component (PC) analysis and binding free energy calculations were combined to probe effect of electrostatic interactions of residues R78, R106 and R126 with inhibitors ZGB, ZGC and IBP on structural stability of three inhibitor/A-FABP complexes. The results indicate that mutation R126A produces significant influence on polar interactions of three inhibitors with A-FABP and these interactions are main force for driving the conformational change of A-FABP. Analyses on hydrogen bond interactions show that the decrease in hydrogen bonding interactions of residues R126 and Y128 with three inhibitors and the increase in that of K58 with inhibitors ZGC and IBP in the R126A mutated systems mostly regulate the conformational changes of A-FABP. This work shows that R126A can generate a significant perturbation on structural stability of A-FABP, which implies that R126 is of significance in inhibitor bindings. We expect that this study can provide a theoretical guidance for design of potent inhibitors targeting A-FABP.Communicated by Ramaswamy H. Sarma 相似文献
952.
Shalini Saxena Maaged Abdullah Dharmarajan Sriram 《Journal of biomolecular structure & dynamics》2013,31(12):3184-3198
MurG (Rv2153c) is a key player in the biosynthesis of the peptidoglycan layer in Mycobacterium tuberculosis (Mtb). This work is an attempt to highlight the structural and functional relationship of Mtb MurG, the three-dimensional (3D) structure of protein was constructed by homology modelling using Discovery Studio 3.5 software. The quality and consistency of generated model was assessed by PROCHECK, ProSA and ERRAT. Later, the model was optimized by molecular dynamics (MD) simulations and the optimized model complex with substrate Uridine-diphosphate-N-acetylglucosamine (UD1) facilitated us to employ structure-based virtual screening approach to obtain new hits from Asinex database using energy-optimized pharmacophore modelling (e-pharmacophore). The pharmacophore model was validated using enrichment calculations, and finally, validated model was employed for high-throughput virtual screening and molecular docking to identify novel Mtb MurG inhibitors. This study led to the identification of 10 potential compounds with good fitness, docking score, which make important interactions with the protein active site. The 25 ns MD simulations of three potential lead compounds with protein confirmed that the structure was stable and make several non-bonding interactions with amino acids, such as Leu290, Met310 and Asn167. Hence, we concluded that the identified compounds may act as new leads for the design of Mtb MurG inhibitors. 相似文献
953.
In order to understand the mechanisms of ligand binding and interaction between two commercial drugs (ligands), zanamivir and oseltamivir and H5N1 Influenza Virus Neuraminidase subtype N1, a three-dimensional model of N1-ligand (GenBank accession no. AAS654617) was initially generated by homology modeling using the 13 high-resolution X-ray structures of neuraminidase N2 and N9 as the template. With the aid of the molecular mechanics and molecular dynamics methods, the final implicit solvent refined model was obtained. It was, then, assessed by PROCHECK, PROSA and VERIFY3D. With this model, a flexible docking study was performed. The results show strong hydrogen bond interactions between the glycerol side chains of zanamivir and Arg29 of the N1. Common hydrogen bonds between the carboxyl groups and Arg279 were found for both drugs. It was also found that the Glu30, Asp62, Arg63, Arg204, Trp310, Tyr313, Glu336, Ile338, Trp348, Ala349 were observed to facilitate the enzyme-ligand non-bonding interactions as they are located within the radius of 5 Å from all atoms of both drugs. Charge distribution was evaluated using the semi-empirical AM1 method. The results show that the total net charges of the –NH side chain of zanamivir is less negative than that of oseltamivir. This is in contrast to what is observed for the amide and alkyl (ether/glycerol) side chains. In comparison of the binding free energies between the X-ray N2-ligand and N9-ligand complexes, N1-ligand binding is found to be less potent than N2 and N9 subtypes, while N2-ligand and N9-ligand are roughly comparable. In addition, it is interesting to observe that the binding free energies for all three subtypes of the zanamivir complexes are lower than those of oseltamivir. 相似文献
954.
Nhuan T. Vu Yoshitaka Moriwaki Jose M. M. Caaveiro Tohru Terada Hiroshi Tsutsumi Itaru Hamachi Kentaro Shimizu Kouhei Tsumoto 《Protein science : a publication of the Protein Society》2013,22(7):942-953
The Isd (iron‐regulated surface determinant) system of the human pathogen Staphylococcus aureus is responsible for the acquisition of heme from the host organism. We recently reported that the extracellular heme receptor IsdH‐NEAT3 captures and transfers noniron antimicrobial porphyrins containing metals in oxidation state (III). However, it is unclear if geometric factors such as the size of the metal (ionic radius) affect binding and transfer of metalloporphyrins. We carried out an ample structural, functional, and thermodynamic analysis of the binding properties of antimicrobial indium(III)‐porphyrin, which bears a much larger metal ion than the iron(III) of the natural ligand heme. The results demonstrate that the NEAT3 receptor recognizes the In(III)‐containing PPIX in a manner very similar to that of heme. Site‐directed mutagenesis identifies Tyr642 as the central element in the recognition mechanism as suggested from the crystal structures. Importantly, the NEAT3 receptor possesses the remarkable ability to capture dimers of metalloporphyrin. Molecular dynamics simulations reveal that IsdH‐NEAT3 does not require conformational changes, or large rearrangements of the residues within its binding site, to accommodate the much larger (heme)2 ligand. We discuss the implications of these findings for the design of potent inhibitors against this family of key receptors of S. aureus. 相似文献
955.
Michelle F. DiLeo Jeremy D. Rouse José A. Dávila Stephen C. Lougheed 《Molecular ecology》2013,22(17):4483-4498
Understanding how gene flow shapes contemporary population structure requires the explicit consideration of landscape composition and configuration. New landscape genetic approaches allow us to link such heterogeneity to gene flow within and among populations. However, the attribution of cause is difficult when landscape features are spatially correlated, or when genetic patterns reflect past events. We use spatial Bayesian clustering and landscape resistance analysis to identify the landscape features that influence gene flow across two regional populations of the eastern massasauga rattlesnake, Sistrurus c. catenatus. Based on spatially explicit simulations, we inferred how habitat distribution modulates gene flow and attempted to disentangle the effects of spatially confounded landscape features. We found genetic clustering across one regional landscape but not the other, and also local differences in the effect of landscape on gene flow. Beyond the effects of isolation‐by‐distance, water bodies appear to underlie genetic differentiation among individuals in one regional population. Significant effects of roads were additionally detected locally, but these effects are possibly confounded with the signal of water bodies. In contrast, we found no signal of isolation‐by‐distance or landscape effects on genetic structure in the other regional population. Our simulations imply that these local differences have arisen as a result of differences in population density or tendencies for juvenile rather than adult dispersal. Importantly, our simulations also demonstrate that the ability to detect the consequences of contemporary anthropogenic landscape features (e.g. roads) on gene flow may be compromised when long‐standing natural features (e.g. water bodies) co‐exist on the landscape. 相似文献
956.
957.
Q. WU N. SEPEHRI A. B. THORNTON-TRUMP M. ALEXANDER 《Computer methods in biomechanics and biomedical engineering》2013,16(3):247-259
A mathematical model has been developed to study the control mechanisms of human trunk movement during walking. The trunk is modeled as a base-excited inverted pendulum with two-degrees of rotational freedom. The base point, corresponding to the bony landmark of the sacrum, can move in three-dimensional space in a general way. Since the stability of upright posture is essential for human walking, a controller has been designed such that the stability of the pendulum about the upright position is guaranteed. The control laws are developed based on Lyapunov' stability theory and include feedforward and linear feedback components. It is found that the feedforward component plays a critical role in keeping postural stability, and the linear feedback component, (resulting from viscoelastic function of the musculoskeletal system) can effectively duplicate the pattern of trunk movement. The mathematical model is validated by comparing the simulation results with those based on gait measurements performed in the Biomechanics Laboratory at the University of Manitoba. 相似文献
958.
T.M. Koch B.D. Reddy P. Zilla 《Computer methods in biomechanics and biomedical engineering》2013,16(2):225-234
This work was concerned with the numerical simulation of the behaviour of aortic valves whose material can be modelled as non-linear elastic anisotropic. Linear elastic models for the valve leaflets with parameters used in previous studies were compared with hyperelastic models, incorporating leaflet anisotropy with pronounced stiffness in the circumferential direction through a transverse isotropic model. The parameters for the hyperelastic models were obtained from fits to results of orthogonal uniaxial tensile tests on porcine aortic valve leaflets. The computational results indicated the significant impact of transverse isotropy and hyperelastic effects on leaflet mechanics; in particular, increased coaptation with peak values of stress and strain in the elastic limit. The alignment of maximum principal stresses in all models follows approximately the coarse collagen fibre distribution found in aortic valve leaflets. The non-linear elastic leaflets also demonstrated more evenly distributed stress and strain which appears relevant to long-term scaffold stability and mechanotransduction. 相似文献
959.
This study evaluated both biosafety levels (BLs) and airborne fungal concentrations in microbiological laboratories in Seoul, Korea. To evaluate biosafety facilities, we used a checklist containing 67 questions in nine categories. We also measured airborne fungal concentration according to the BLs. Airborne fungal concentrations were higher in BL-1 facilities (240 CFU/m3) than in BL-2 facilities (25 CFU/m3). The airborne fungal concentrations significantly differed among the laboratories that were graded as poor, fair, and good. Especially, a significant negative correlation was observed between the airborne fungal concentrations and the biosafety levels (p = .001). We recommend that the guidelines of biosafety be followed to improve laboratory environment. 相似文献
960.
We have demonstrated label-free THz sensing of living body-related molecular binding using a thin metallic mesh and a polyvinylidene difluoride (PVDF) membrane. Metallic meshes in the THz region are designed for anomalous transmission phenomena derived from a resonant excitation of surface waves. Additionally, they are designed to have a sharp dip in transmittance. The metallic mesh is very sensitive to a change of the refractive index of materials attached to the metallic mesh. In this paper, we report sensing of interactions between lectin and sugar using this technique. We found that the dip frequency shift, transmittance attenuation of the dip frequency, and peak shift of the derivative spectrum of the phase shift depend on the bonding amount of lectin–sugar interactions. We also applied this technique to detect avidin–biotin interactions, leading to the detection of a small amount of biotin (0.17 pg/mm2). 相似文献