scholarly journals Does Antibody Stabilize the Ligand Binding in GP120 of HIV-1 Envelope Protein? Evidence from MD Simulation

Molecules ◽  
2021 ◽  
Vol 26 (1) ◽  
pp. 239
Author(s):  
Shalini Yadav ◽  
Vishnudatt Pandey ◽  
Rakesh Kumar Tiwari ◽  
Rajendra Prasad Ojha ◽  
Kshatresh Dutta Dubey
Keyword(s):  
Conformational Dynamics ◽  
Md Simulations ◽  
Conformational Flexibility ◽  
Free Energy Calculations ◽  
Titration Calorimetry ◽  
Entry Inhibitors ◽  
Binding Enthalpy ◽  
Dynamics Simulations ◽  
Hiv 1 ◽  
Good Agreement

CD4-mimetic HIV-1 entry inhibitors are small sized molecules which imitate similar conformational flexibility, in gp120, to the CD4 receptor. However, the mechanism of the conformational flexibility instigated by these small sized inhibitors is little known. Likewise, the effect of the antibody on the function of these inhibitors is also less studied. In this study, we present a thorough inspection of the mechanism of the conformational flexibility induced by a CD4-mimetic inhibitor, NBD-557, using Molecular Dynamics Simulations and free energy calculations. Our result shows the functional importance of Asn425 in substrate induced conformational dynamics in gp120. The MD simulations of Asn425Gly mutant provide a less dynamic gp120 in the presence of NBD-557 without incapacitating the binding enthalpy of NBD-557. The MD simulations of complexes with the antibody clearly show the enhanced affinity of NBD-557 due to the presence of the antibody, which is in good agreement with experimental Isothermal Titration Calorimetry results (Biochemistry2006, 45, 10973–10980).

scholarly journals Does Antibody Stabilize the Ligand Binding in GP120 of HIV-1 Envelope Protein? Evidence from MD Simulation

2019 ◽  
Author(s):  
Vishnudatt Pandey ◽  
Rakesh Kumar Tiwari ◽  
Rajendra Prasad Ojha ◽  
Kshatresh Dutta Dubey
Keyword(s):  
Conformational Dynamics ◽  
Md Simulations ◽  
Conformational Flexibility ◽  
Free Energy Calculations ◽  
Titration Calorimetry ◽  
Entry Inhibitors ◽  
Binding Enthalpy ◽  
Dynamics Simulations ◽  
Hiv 1 ◽  
Good Agreement

AbstractCD4-mimetic HIV-1 entry inhibitors are small sized molecules which imitate similar conformational flexibility in gp120 as CD4 receptor, the mechanism of the conformational flexibility instigated by these small sized inhibitors, however, is little known. Likewise, the effect of the antibody on the function of these inhibitors is also less studied. In this study, we present a thorough inspection of the mechanism of the conformational flexibility induced by a CD4-mimetic inhibitor, NBD-557, using Molecular Dynamics Simulations and free energy calculations. Our result shows a functional importance of Asn239 in substrate instigated conformational dynamics in gp120. The MD simulations of Asn239Gly mutant provide a less dynamic gp120 in the presence of NBD-557 without incapacitating the binding enthalpy of NBD-557. The MD simulations of complex with the antibody clearly shows the enhanced affinity of NBD-557 due to the presence of the antibody which is in good agreement with experimental Isothermal Titration Calorimetry results (Biochemistry2006,45, 10973-10980).

scholarly journals Molecular dynamics simulations reveal distinct differences in conformational dynamics and thermodynamics between the unliganded and CD4-bound states of HIV-1 gp120

2020 ◽  
Vol 22 (10) ◽  
pp. 5548-5560
Author(s):  
Yi Li ◽  
Lei Deng ◽  
Jing Liang ◽  
Guang-Heng Dong ◽  
Yuan-Ling Xia ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Bound States ◽  
Conformational Dynamics ◽  
Immunological Properties ◽  
Dynamics Simulations ◽  
Hiv Gp120 ◽  
Hiv 1

Large changes in dynamics and thermodynamics of gp120 upon CD4 binding account for the functional and immunological properties of HIV/gp120.

scholarly journals Effects of CD4 Binding on Conformational Dynamics, Molecular Motions, and Thermodynamics of HIV-1 gp120

2019 ◽  
Vol 20 (2) ◽  
pp. 260 ◽  
Author(s):  
Yi Li ◽  
Lei Deng ◽  
Li-Quan Yang ◽  
Peng Sang ◽  
Shu-Qun Liu
Keyword(s):  
Free Energy ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Cell Receptor ◽  
Molecular Motions ◽  
Host Cell Receptor ◽  
Gp120 Core ◽  
Glycoprotein Gp120 ◽  
The Stability ◽  
Hiv 1

Human immunodeficiency virus type-1 (HIV-1) infection is triggered by its envelope (Env) glycoprotein gp120 binding to the host-cell receptor CD4. Although structures of Env/gp120 in the liganded state are known, detailed information about dynamics of the liganded gp120 has remained elusive. Two structural models, the CD4-free gp120 and the gp120-CD4 complex, were subjected to µs-scale multiple-replica molecular dynamics (MD) simulations to probe the effects of CD4 binding on the conformational dynamics, molecular motions, and thermodynamics of gp120. Comparative analyses of MD trajectories in terms of structural deviation and conformational flexibility reveal that CD4 binding effectively suppresses the overall conformational fluctuations of gp120. Despite the largest fluctuation amplitude of the V1/V2 region in both forms of gp120, the presence of CD4 prevents it from approaching the gp120 core. Comparison of the constructed free energy landscapes (FELs) shows that CD4 binding reduces the conformational entropy and conformational diversity while enhancing the stability of gp120. Further comparison of the representative structures extracted from free energy basins/minima of FELs reveals that CD4 binding weakens the reorientation ability of V1/V2 and hence hinders gp120 from transitioning out of the liganded state to the unliganded state. Therefore, locking gp120 conformation via restraining V1/V2 reorientation with small molecules seems to be a promising strategy to control HIV-1 infection. Our computer simulation results support the conformational selection mechanism for CD4 binding to gp120 and facilitate the understanding of HIV-1 immune evasion mechanisms.

scholarly journals Extended Peptide Basis Set for Variational Markov Models: Secondary Structure, Orthonormality, and Undersampled Transitions

2018 ◽  
Author(s):  
Louis Martini ◽  
Bettina Keller
Keyword(s):  
Markov Models ◽  
Probability Distributions ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Peptide Sequence ◽  
Basis Set ◽  
Variational Models ◽  
Helix Formation ◽  
Α Helix ◽  
Dynamics Simulations

<div><div><div><p>The variational approach to conformational dynamics offers a systematic way to con- struct kinetic models from molecular dynamics simulations, using an arbitrary set of basis functions. We have recently proposed a basis set for peptide systems that only depends on the sequence of amino acids in the system. This basis set is not data- driven and can therefore be used to compare models for different MD simulations. Here we introduce an orthonormality condition for this basis set as a requirement for the variational models to remain directly interpretable. The orthonormality condi- tion naturally leads to a way of detecting correlations between the sampled marginal stationary probability distributions at each residue in the peptide sequence. We show how these correlations emerge from either undersampled transitions or from inher- ent dynamical dependencies between the residues. Our basis set relies on a tensor structure obtained from residue-centered ansatz functions. We demonstrate that this structure is sufficient to model both β-sheet and α-helix formation in peptides.</p></div></div></div>

scholarly journals In Silico Identification of Novel Aromatic Compounds as Potential HIV-1 Entry Inhibitors Mimicking Cellular Receptor CD4

Viruses ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 746 ◽  
Author(s):  
Alexander M. Andrianov ◽  
Grigory I. Nikolaev ◽  
Yuri V. Kornoushenko ◽  
Wei Xu ◽  
Shibo Jiang ◽  
...  
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Cellular Receptor ◽  
Dynamic Simulations ◽  
Entry Inhibitors ◽  
Fusion Inhibitors ◽  
Gp120 Protein ◽  
Hiv 1

Despite recent progress in the development of novel potent HIV-1 entry/fusion inhibitors, there are currently no licensed antiviral drugs based on inhibiting the critical interactions of the HIV-1 envelope gp120 protein with cellular receptor CD4. In this connection, studies on the design of new small-molecule compounds able to block the gp120-CD4 binding are still of great value. In this work, in silico design of drug-like compounds containing the moieties that make the ligand active towards gp120 was performed within the concept of click chemistry. Complexes of the designed molecules bound to gp120 were then generated by molecular docking and optimized using semiempirical quantum chemical method PM7. Finally, the binding affinity analysis of these ligand/gp120 complexes was performed by molecular dynamic simulations and binding free energy calculations. As a result, five top-ranking compounds that mimic the key interactions of CD4 with gp120 and show the high binding affinity were identified as the most promising CD4-mimemic candidates. Taken together, the data obtained suggest that these compounds may serve as promising scaffolds for the development of novel, highly potent and broad anti-HIV-1 therapeutics.

Interaction between gp120 and ligand in HIV-1 env protein: Molecular dynamics simulations and binding free energy calculations

2019 ◽  
Author(s):  
Vishnudatt Pandey ◽  
Gargi Tiwari ◽  
Vijaya Shri Mall ◽  
Rakesh Kumar Tiwari ◽  
Rajendra Prasad Ojha
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Env Protein ◽  
Dynamics Simulations ◽  
Protein Molecular Dynamics ◽  
Hiv 1

Molecular Simulations to Rationalize Humanized Ab2/3H6 Activity

2011 ◽  
Vol 64 (7) ◽  
pp. 900 ◽  
Author(s):  
Anita de Ruiter ◽  
Alexander Mader ◽  
Renate Kunert ◽  
Chris Oostenbrink
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Heavy Chain ◽  
Free Energy Calculations ◽  
Binding Affinities ◽  
Dynamics Simulations ◽  
Idiotypic Antibody ◽  
Mouse Antibody ◽  
Hiv 1

The murine anti-idiotypic antibody 3H6 (Ab2/3H6) is directed against the human 2F5 antibody, which is capable of neutralizing HIV-1. Recently, four humanized Ab2/3H6 models have been developed in order to reduce the risk of human anti-mouse antibody (HAMA) responses in case of administration to humans. In this study, molecular dynamics simulations were performed on these models as well as on the murine Ab2/3H6 in solution and bound to 2F5, in order to rationalize the differences in binding affinities of the models towards 2F5. Analysis of these simulations suggested that the orientation and dynamics of the residues TYR54 and TYR103 of the heavy chain of Ab2/3H6 play an important role in these differences. Subsequently, the contribution of these residues to the binding affinity was quantified by applying free energy calculations.

scholarly journals Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4

2018 ◽  
Author(s):  
D. R. Kattnig ◽  
C. Nielsen ◽  
I. A. Solov’yov
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Large Scale ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Quantum Processes ◽  
Helical Segment ◽  
High Betweenness ◽  
Dynamics Simulations ◽  
Fad Binding

AbstractBirds appear to be equipped with a light-dependent, radical-pair-based magnetic compass that relies on truly quantum processes. While the identity of the sensory protein has remained speculative, cryptochrome 4 has recently been identified as the most auspicious candidate. Here, we report on allatom molecular dynamics (MD) simulations addressing the structural reorganisations that accompany the photoreduction of the flavin cofactor in a model of the European robin cryptochrome 4 (ErCry4). Extensive MD simulations reveal that the photo-activation of ErCry4 induces large-scale conformational changes on short (hundreds of nanoseconds) timescales. Specifically, the photo-reduction is accompanied with the release of the C-terminal tail, structural rearrangements in the vicinity of the FAD-binding site, and the noteworthy formation of an α-helical segment at the N-terminal part. Some of these rearrangements appear to expose potential phosphorylation sites. We describe the conformational dynamics of the protein using a graph-based approach that is informed by the adjacency of residues and the correlation of their local motions. This approach reveals densely coupled reorganisation communities, which facilitate an efficient signal transduction due to a high density of hubs. These communities are interconnected by a small number of highly important residues characterized by high betweenness centrality. The network approach clearly identifies the sites restructuring upon photoactivation, which appear as protrusions or delicate bridges in the reorganisation network. We also find that, unlike in the homologous cryptochrome from D. melanogaster, the release of the C-terminal domain does not appear to be correlated with the transposition of a histidine residue close to the FAD cofactor.

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