Explicit solvent dynamics and energetics of HIV-1 protease flap opening and closing

2010 ◽  
Vol 78 (14) ◽  
pp. 2873-2885 ◽  
Author(s):  
S. Kashif Sadiq ◽  
Gianni De Fabritiis
Keyword(s):  
Explicit Solvent ◽  
Solvent Dynamics ◽  
Opening And Closing ◽  
Hiv 1

scholarly journals The Role of Displacing Confined Solvent in the Conformational Equilibrium of β-Cyclodextrin

2019 ◽  
Author(s):  
Peng He ◽  
Sheila Sarkar ◽  
Emilio Gallicchio ◽  
Tom Kurtzman ◽  
Lauren Wickstrom
Keyword(s):  
Conformational Equilibrium ◽  
Implicit Solvent ◽  
Theory Analysis ◽  
State Behavior ◽  
Generalized Born ◽  
Solvent Models ◽  
Explicit Solvent ◽  
Dynamics Simulations ◽  
Opening And Closing

<p>This study investigates the role of hydration and its relationship to the conformational equilibrium of the host molecule β-cyclodextrin. Molecular dynamics simulations indicate that the unbound β-cyclodextrin exhibits two state behavior in explicit solvent due to the opening and closing of its cavity. In implicit solvent, these transitions are not observed and there is one dominant conformation of β-cyclodextrin with an open cavity. Based on these observations, we investigate the hypothesis that the expulsion of thermodynamically unfavorable water molecules into the bulk plays an important role in controlling the accessibility of the closed macrostate at room temperature. We compare the results of the molecular mechanics analytical generalized Born plus non-polar solvation approach to those obtained through Grid Inhomogeneous Solvation Theory analysis with explicit solvation to elucidate the thermodynamic forces at play. The calculations help to illustrate the deficiencies of continuum solvent models and demonstrate the key role of the thermodynamics of enclosed hydration in driving the conformational equilibrium of molecules in solution. </p>

scholarly journals Beyond Continuum Solvent Models in Computational Homogeneous Catalysis

2021 ◽  
Author(s):  
Gantulga Norjmaa ◽  
Gregori Ujaque ◽  
Agustí Lledós
Keyword(s):  
Homogeneous Catalysis ◽  
Solvent Effects ◽  
Solvent Polarity ◽  
Quantum Mechanical ◽  
Solvent Models ◽  
Quantum Mechanical Description ◽  
Explicit Solvent ◽  
Solvent Dynamics ◽  
Solvent Molecules ◽  
Continuum Solvent Models

AbstractIn homogeneous catalysis solvent is an inherent part of the catalytic system. As such, it must be considered in the computational modeling. The most common approach to include solvent effects in quantum mechanical calculations is by means of continuum solvent models. When they are properly used, average solvent effects are efficiently captured, mainly those related with solvent polarity. However, neglecting atomistic description of solvent molecules has its limitations, and continuum solvent models all alone cannot be applied to whatever situation. In many cases, inclusion of explicit solvent molecules in the quantum mechanical description of the system is mandatory. The purpose of this article is to highlight through selected examples what are the reasons that urge to go beyond the continuum models to the employment of micro-solvated (cluster-continuum) of fully explicit solvent models, in this way setting the limits of continuum solvent models in computational homogeneous catalysis. These examples showcase that inclusion of solvent molecules in the calculation not only can improve the description of already known mechanisms but can yield new mechanistic views of a reaction. With the aim of systematizing the use of explicit solvent models, after discussing the success and limitations of continuum solvent models, issues related with solvent coordination and solvent dynamics, solvent effects in reactions involving small, charged species, as well as reactions in protic solvents and the role of solvent as reagent itself are successively considered.

scholarly journals Closing and Opening Holes in the Glycan Shield of HIV-1 Envelope Glycoprotein SOSIP Trimers Can Redirect the Neutralizing Antibody Response to the Newly Unmasked Epitopes

2018 ◽  
Vol 93 (4) ◽  
Author(s):  
Rajesh P. Ringe ◽  
Pavel Pugach ◽  
Christopher A. Cottrell ◽  
Celia C. LaBranche ◽  
Gemma E. Seabright ◽  
...  
Keyword(s):  
Antibody Response ◽  
Viral Entry ◽  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Tier 2 ◽  
Protein Surfaces ◽  
Opening And Closing ◽  
Glycan Site ◽  
Hiv 1

ABSTRACTIn HIV-1 vaccine research, native-like, soluble envelope glycoprotein SOSIP trimers are widely used for immunizing animals. The epitopes of autologous neutralizing antibodies (NAbs) induced by the BG505 and B41 SOSIP trimers in rabbits and macaques have been mapped to a few holes in the glycan shields that cover most of the protein surfaces. For BG505 trimers, the dominant autologous NAb epitope in rabbits involves residues that line a cavity caused by the absence of a glycan at residue 241. Here, we blocked this epitope in BG505 SOSIPv4.1 trimer immunogens by knocking in an N-linked glycan at residue 241. We then opened holes elsewhere on the trimer by knocking out single N-linked glycans at residues 197, 234, 276, 332, and 355 and found that NAb responses induced by the 241-glycan-bearing BG505 trimers were frequently redirected to the newly opened sites. The strongest evidence for redirection of the NAb response to neoepitopes, through the opening and closing of glycan holes, was obtained from trimer immunogen groups with the highest occupancy of the N241 site. We also attempted to knock in the N289-glycan to block the sole autologous NAb epitope on the B41 SOSIP.v4.1 trimer. Although a retrospective analysis showed that the new N289-glycan site was substantially underoccupied, we found some evidence for redirection of the NAb response to a neoepitope when this site was knocked in and the N356-glycan site knocked out. In neither study, however, was redirection associated with increased neutralization of heterologous tier 2 viruses.IMPORTANCEEngineered SOSIP trimers mimic envelope-glycoprotein spikes, which stud the surface of HIV-1 particles and mediate viral entry into cells. When used for immunizing test animals, they elicit antibodies that neutralize resistant sequence-matched HIV-1 isolates. These neutralizing antibodies recognize epitopes in holes in the glycan shield that covers the trimer. Here, we added glycans to block the most immunogenic neutralization epitopes on BG505 and B41 SOSIP trimers. In addition, we removed selected other glycans to open new holes that might expose new immunogenic epitopes. We immunized rabbits with the various glycan-modified trimers and then dissected the specificities of the antibody responses. Thus, in principle, the antibody response might be diverted from one site to a more cross-reactive one, which would help in the induction of broadly neutralizing antibodies by HIV-1 vaccines based on envelope glycoproteins.

Substrate Binding Mechanism of HIV-1 Protease from Explicit-Solvent Atomistic Simulations

2009 ◽  
Vol 131 (33) ◽  
pp. 11811-11818 ◽  
Author(s):  
Fabio Pietrucci ◽  
Fabrizio Marinelli ◽  
Paolo Carloni ◽  
Alessandro Laio
Keyword(s):  
Substrate Binding ◽  
Atomistic Simulations ◽  
Binding Mechanism ◽  
Explicit Solvent ◽  
Hiv 1

scholarly journals HIV-1 NC Protein Modifies Opening and Closing Kinetics of TAR RNA Hairpin

2011 ◽  
Vol 100 (3) ◽  
pp. 231a
Author(s):  
Micah J. McCauley ◽  
Ioulia Rouzina ◽  
Kelly Hoadley ◽  
Karin Musier-Forsyth ◽  
Mark C. Williams
Keyword(s):  
Tar Rna ◽  
Opening And Closing ◽  
Rna Hairpin ◽  
Kinetics Of ◽  
Hiv 1

scholarly journals The Role of Displacing Confined Solvent in the Conformational Equilibrium of β-Cyclodextrin

2019 ◽  
Author(s):  
Peng He ◽  
Sheila Sarkar ◽  
Emilio Gallicchio ◽  
Tom Kurtzman ◽  
Lauren Wickstrom
Keyword(s):  
Conformational Equilibrium ◽  
Implicit Solvent ◽  
Theory Analysis ◽  
State Behavior ◽  
Generalized Born ◽  
Solvent Models ◽  
Explicit Solvent ◽  
Dynamics Simulations ◽  
Opening And Closing

<p>This study investigates the role of hydration and its relationship to the conformational equilibrium of the host molecule β-cyclodextrin. Molecular dynamics simulations indicate that the unbound β-cyclodextrin exhibits two state behavior in explicit solvent due to the opening and closing of its cavity. In implicit solvent, these transitions are not observed and there is one dominant conformation of β-cyclodextrin with an open cavity. Based on these observations, we investigate the hypothesis that the expulsion of thermodynamically unfavorable water molecules into the bulk plays an important role in controlling the accessibility of the closed macrostate at room temperature. We compare the results of the molecular mechanics analytical generalized Born plus non-polar solvation approach to those obtained through Grid Inhomogeneous Solvation Theory analysis with explicit solvation to elucidate the thermodynamic forces at play. The calculations help to illustrate the deficiencies of continuum solvent models and demonstrate the key role of the thermodynamics of enclosed hydration in driving the conformational equilibrium of molecules in solution. </p>

Ultrastructural observations of human monocytes infected with HIV-1

1991 ◽  
Vol 49 ◽  
pp. 108-109
Author(s):  
James K. Koehler ◽  
Steven G. Reed ◽  
Joao S. Silva
Keyword(s):  
Gradient Centrifugation ◽  
Virus Production ◽  
Human Monocyte ◽  
Red Cross ◽  
Human Monocytes ◽  
Blood Monocytes ◽  
Hiv Replication ◽  
Electron Microscopic ◽  
Ultrastructural Studies ◽  
Hiv 1

As part of a larger study involving the co-infection of human monocyte cultures with HIV and protozoan parasites, electron microscopic observations were made on the course of HIV replication and infection in these cells. Although several ultrastructural studies of the cytopathology associated with HIV infection have appeared, few studies have shown the details of virus production in “normal,” human monocytes/macrophages, one of the natural targets of the virus, and suspected of being a locus of quiescent virus during its long latent period. In this report, we detail some of the interactions of developing virons with the membranes and organelles of the monocyte host.Peripheral blood monocytes were prepared from buffy coats (Portland Red Cross) by Percoll gradient centrifugation, followed by adherence to cover slips. 90-95% pure monocytes were cultured in RPMI with 5% non-activated human AB serum for four days and infected with 100 TCID50/ml of HIV-1 for four hours, washed and incubated in fresh medium for 14 days.

Astrocytic adhesion molecules are increased in HIV-1-associated cognitive/motor complex

1997 ◽  
Vol 23 (3) ◽  
pp. 83-92 ◽  
Author(s):  
D. Seilhean ◽  
A. Dzia-Lepfoundzou ◽  
V. Sazdovitch ◽  
B. Cannella ◽  
C. S. Raine ◽  
...  
Keyword(s):  
Adhesion Molecules ◽  
Motor Complex ◽  
Hiv 1
Sign in / Sign up

Export Citation Format

Share Document