Molecular modeling on human CCR5 receptors and complex with CD4 antigens and HIV-1 envelope glycoprotein gp120

AIM: To investigate the interaction between human CCR5 receptors (CCR5) and HIV-1 envelope glycoprotein gp120 (HIV-1 gp120) and HIV-1 receptor CD4 antigens (CD4). METHODS: The structurally con served regions (SCR) of human CCR5 was built by the SYBYL/Biopolymer module using the corresponding transmembrane (TM) domain of bacteriorhodopsin (bR) as the template. The coordinates for amino-ter minal residue sequence, and carboxyl-terminal residue sequence, extracellular and cytoplasmic loops were generated using LOOP SEARCH algorithm. Subsequently the structural model was merged into the complex with HIV-1 gp120 and CD4. RESULTS: Human CCR5 interacted with both an HIV-1 gp120 and CD4. The N-terminal residues (especially Met1 and Gln4) of human CCR5, contacted with CD4 residues, mainly 7Nith one span (56 - 59) of CD4 in electrostatic interaction and hydrogen-bonds. The binding sites of human CCR5 were buried in a hydrophobic center surrounded by a highly basic periphery. On the other hand, direct interatomic contacts were made between ? CCR5 residues and 6 gp120 amino-acid residues, which included van der Waals contacts, hydrophobic interaction, and hydrogen bonds. CONCLUSION: The interaction model should be helpful for rational design of novel anti-HIV drugs.

Structural and functional characterization of the human CCR5 receptor in complex with HIV gp120 envelope glycoprotein and CD4 receptor by molecular modeling studies

The entry of human immunodeficiency virus (HIV) into cells depends on a sequential interaction of the gp120 envelope glycoprotein with the cellular receptors CD4 and members of the chemokine receptor family. The CC chemokine receptor CCR5 is such a receptor for several chemokines and a major coreceptor for the entry of R5 HIV type-1 (HIV-1) into cells. Although many studies focus on the interaction of CCR5 with HIV-1, the corresponding interaction sites in CCR5 and gp120 have not been matched. Here we used an approach combining protein structure modeling, docking and molecular dynamics simulation to build a series of structural models of the CCR5 in complexes with gp120 and CD4. Interactions such as hydrogen bonds, salt bridges and van der Waals contacts between CCR5 and gp120 were investigated. Three snapshots of CCR5-gp120-CD4 models revealed that the initial interactions of CCR5 with gp120 are involved in the negatively charged N-terminus (Nt) region of CCR5 and positively charged bridging sheet region of gp120. Further interactions occurred between extracellular loop2 (ECL2) of CCR5 and the base of V3 loop regions of gp120. These interactions may induce the conformational changes in gp120 and lead to the final entry of HIV into the cell. These results not only strongly support the two-step gp120-CCR5 binding mechanism, but also rationalize extensive biological data about the role of CCR5 in HIV-1 gp120 binding and entry, and may guide efforts to design novel inhibitors.

Characterize dynamic conformational space of human CCR5 extracellular domain by molecular modeling and molecular dynamics simulation

The chemokine receptor CCR5 is the receptor for several chemokines and major coreceptor for R5 human immunodeficiency virus type-1 strains entry into cell. Three-dimensional models of CCR5 were built by using homology modeling approach and 1 ns molecular dynamics (MD) simulation, because studies of site-directed mutagenesis and chimeric receptors have indicated that the N-terminus (Nt) and extracellular loops (ECLs) of CCR5 are important for ligands binding and viral fusion and entry, special attention was focused on disulfide bond function, conformational flexibility, hydrogen bonding, electrostatic interactions, and solvent-accessible surface area of Nt and ECLs of this protein part. We found that the extracellular segments of CCR5 formed a well-packet globular domain with complex interactions occurred between them in a majority of time of MID simulation, but Nt region could protrude from this domain sometimes. The disulfide bond Cys20-Cys269 is essential in controlling specific orientation of Nt region and maintaining conformational integrity of extracellular domain. RMS comparison analysis between conformers revealed the ECL1 of CCR5 stays relative rigid, whereas the ECL2 and Nt are rather flexible. Solvent-accessible surface area calculations indicated that the charged residues within Nt and ECL2 are often exposed to solvent. Integrating these results with available experimental data, a two-step gp120-CCR5 binding mechanism was proposed. The dynamic interaction of CCR5 extracellular domain with gp120 was emphasized. (C) 2004 Elsevier B.V. All rights reserved.

Designing inclusive interfaces through user modeling and simulation

Elderly and disabled people can be hugely benefited through the advancement of modern electronic devices, as those can help them to engage more fully with the world. However, existing design practices often isolate elderly or disabled users by considering them as users with special needs. This article presents a simulator that can reflect problems faced by elderly and disabled users while they use computer, television, and similar electronic devices. The simulator embodies both the internal state of an application and the perceptual, cognitive, and motor processes of its user. It can help interface designers to understand, visualize, and measure the effect of impairment on interaction with an interface. Initially a brief survey of different user modeling techniques is presented, and then the existing models are classified into different categories. In the context of existing modeling approaches the work on user modeling is presented for people with a wide range of abilities. A few applications of the simulator, which shows the predictions are accurate enough to make design choices and point out the implication and limitations of the work, are also discussed. © 2012 Copyright Taylor and Francis Group, LLC.

Seismic response of stone masonry spires: Analytical modeling

Stone masonry spires are vulnerable to seismic loading. Computational methods are often used to predict the dynamic linear elastic response of masonry towers and spires, but this approach is only applicable until the first masonry joint begins to open, limiting the ability to predict collapse. In this paper, analytical modeling is used to investigate the uplift, rocking and collapse of stone spires. General equations for static equilibrium of the spire under lateral acceleration are first presented, and provide a reasonable lower bound for predicting collapse. The dynamic response is then considered through elastic modal analysis and rigid body rocking. Together, these methods are used to provide uplift curves and single impulse overturning collapse curves for a complete range of possible spire geometries. Results are used to evaluate the historic collapse of two specific stone spires. © 2012 Elsevier Ltd.

Seismic response of stone masonry spires: Computational and experimental modeling

Analytical methods provide a global context from which to understand the dynamics of stone spires, but computational and experimental methods are useful to predict more specific behavior of multiple block structures. In this paper, the spire of St. Mary Magdalene church in Waltham-on-the-Wolds, UK, which was damaged in the 2008 Lincolnshire Earthquake, is used as a case study. Both a physical model and a discrete element computational model of the spire were created and used to investigate collapse under constant horizontal acceleration, impulse base motion, and earthquake ground motion. Results indicate that the global behavior compares well with analytical modeling, but local block displacements evident in DEM and experimental results also reduce the stability of the structure. In this context, the observed damage to St. Mary Magdalene church is evaluated and discussed. © 2012 Elsevier Ltd.