scholarly journals MxB restricts HIV-1 by targeting the tri-hexamer interface of the viral capsid

2018 ◽  
Author(s):  
Sarah Sierra Smaga ◽  
Chaoyi Xu ◽  
Brady James Summers ◽  
Katherine Marie Digianantonio ◽  
Juan Roberto Perilla ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Viral Genome ◽  
Specific Interaction ◽  
Md Simulations ◽  
Building Blocks ◽  
Binding Pocket ◽  
Restriction Factor ◽  
Antiviral Protein ◽  
N Terminus ◽  
Hiv 1

AbstractMyxovirus resistance protein B (MxB) is an interferon-inducible restriction factor of HIV-1 that blocks nuclear import of the viral genome. Evidence suggests that MxB recognizes higher-order interfaces of the HIV capsid lattice, but the mechanistic details of this interaction are not known. Previous studies have mapped the restriction activity of MxB to its N-terminus encompassing a triple arginine motif11RRR13. Here we demonstrate a direct and specific interaction between the MxB N-terminus and helical assemblies of HIV-1 capsid protein (CA) using highly purified recombinant proteins. We performed thorough mutagenesis to establish the detailed molecular requirements for the CA interaction with MxB. The results map MxB binding to the interface of three CA hexamers, specifically interactions between positively charged MxB N-terminal residues and negatively charged CA residues. Our crystal structures show that the CA mutations affecting MxB interaction and restriction do not alter the conformation of capsid assembly. In addition, 30 microsecond long all-atom molecular dynamics (MD) simulations of the complex between the MxB N-terminus and the HIV CA tri-hexamer interface show persistent MxB binding and identify a MxB-binding pocket surrounded by three CA hexamers. These results establish the molecular details of the binding of a lattice-sensing host factor onto HIV capsid, and provide insight into how MxB recognizes HIV capsid for the restriction of HIV-1 infection.Author summaryThe human antiviral protein MxB is a restriction factor that fights HIV infection. Previous experiments have demonstrated that MxB targets the HIV capsid, a protein shell that protects the viral genome. To make the conical shaped capsid, HIV CA proteins are organized into a lattice composed of hexamer and pentamer building blocks, providing many interfaces for host proteins to recognize. Through extensive biochemical and biophysical studies and molecular dynamics simulations, we show that MxB is targeting the HIV capsid by recognizing the region created at the intersection of three CA hexamers. We are further able to map this interaction to a few CA residues, located in a negatively-charged well at the interface between the three CA hexamers. This work provides detailed residue-level mapping of the targeted capsid interface and how MxB interacts. This information could inspire the development of capsid-targeting therapies for HIV.

scholarly journals Simulated Breathing: Application of Molecular Dynamics Simulations to Pulmonary Lung Surfactant

Symmetry ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1259
Author(s):  
Maksymilian Dziura ◽  
Basel Mansour ◽  
Mitchell DiPasquale ◽  
P. Charukeshi Chandrasekera ◽  
James W. Gauld ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Pulmonary Surfactant ◽  
Lung Surfactant ◽  
Protein Composition ◽  
Md Simulations ◽  
Building Blocks ◽  
Future Research ◽  
Total Composition ◽  
Protein Components ◽  
Dynamics Simulations

In this review, we delve into the topic of the pulmonary surfactant (PS) system, which is present in the respiratory system. The total composition of the PS has been presented and explored, from the types of cells involved in its synthesis and secretion, down to the specific building blocks used, such as the various lipid and protein components. The lipid and protein composition varies across species and between individuals, but ultimately produces a PS monolayer with the same role. As such, the composition has been investigated for the ways in which it imposes function and confers peculiar biophysical characteristics to the system as a whole. Moreover, a couple of theories/models that are associated with the functions of PS have been addressed. Finally, molecular dynamic (MD) simulations of pulmonary surfactant have been emphasized to not only showcase various group’s findings, but also to demonstrate the validity and importance that MD simulations can have in future research exploring the PS monolayer system.

scholarly journals Dynamic regulation of HIV-1 capsid interaction with the restriction factor TRIM5α identified by magic-angle spinning NMR and molecular dynamics simulations

2018 ◽  
Vol 115 (45) ◽  
pp. 11519-11524 ◽  
Author(s):  
Caitlin M. Quinn ◽  
Mingzhang Wang ◽  
Matthew P. Fritz ◽  
Brent Runge ◽  
Jinwoo Ahn ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Building Blocks ◽  
Magic Angle Spinning ◽  
Magic Angle ◽  
Capsid Assembly ◽  
Dynamic Regulation ◽  
Angle Spinning ◽  
Dynamics Simulations ◽  
Hiv 1

The host factor protein TRIM5α plays an important role in restricting the host range of HIV-1, interfering with the integrity of the HIV-1 capsid. TRIM5 triggers an antiviral innate immune response by functioning as a capsid pattern recognition receptor, although the precise mechanism by which the restriction is imposed is not completely understood. Here we used an integrated magic-angle spinning nuclear magnetic resonance and molecular dynamics simulations approach to characterize, at atomic resolution, the dynamics of the capsid’s hexameric and pentameric building blocks, and the interactions with TRIM5α in the assembled capsid. Our data indicate that assemblies in the presence of the pentameric subunits are more rigid on the microsecond to millisecond timescales than tubes containing only hexamers. This feature may be of key importance for controlling the capsid’s morphology and stability. In addition, we found that TRIM5α binding to capsid induces global rigidification and perturbs key intermolecular interfaces essential for higher-order capsid assembly, with structural and dynamic changes occurring throughout the entire CA polypeptide chain in the assembly, rather than being limited to a specific protein-protein interface. Taken together, our results suggest that TRIM5α uses several mechanisms to destabilize the capsid lattice, ultimately inducing its disassembly. Our findings add to a growing body of work indicating that dynamic allostery plays a pivotal role in capsid assembly and HIV-1 infectivity.

scholarly journals Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Pierrick Craveur ◽  
Anna T. Gres ◽  
Karen A. Kirby ◽  
Dandan Liu ◽  
John A. Hammond ◽  
...  
Keyword(s):  
Viral Replication ◽  
Specific Interaction ◽  
Binding Pocket ◽  
Core Stability ◽  
Host Cells ◽  
Capsid Assembly ◽  
Dynamic Simulations ◽  
Virus Like Particle ◽  
Hiv 1

ABSTRACTHIV-1 capsid protein (CA) plays critical roles in both early and late stages of the viral replication cycle. Mutagenesis and structural experiments have revealed that capsid core stability significantly affects uncoating and initiation of reverse transcription in host cells. This has led to efforts in developing antivirals targeting CA and its assembly, although none of the currently identified compounds are used in the clinic for treatment of HIV infection. A specific interaction that is primarily present in pentameric interfaces in the HIV-1 capsid core was identified and is reported to be important for CA assembly. This is shown by multidisciplinary characterization of CA site-directed mutants using biochemical analysis of virus-like particle formation, transmission electron microscopy ofin vitroassembly, crystallographic studies, and molecular dynamic simulations. The data are consistent with a model where a hydrogen bond between CA residues E28 and K30′ from neighboring N-terminal domains (CANTDs) is important for CA pentamer interactions during core assembly. This pentamer-preferred interaction forms part of anN-terminaldomaininterface (NDI) pocket that is amenable to antiviral targeting.IMPORTANCEPrecise assembly and disassembly of the HIV-1 capsid core are key to the success of viral replication. The forces that govern capsid core formation and dissociation involve intricate interactions between pentamers and hexamers formed by HIV-1 CA. We identified one particular interaction between E28 of one CA and K30′ of the adjacent CA that appears more frequently in pentamers than in hexamers and that is important for capsid assembly. Targeting the corresponding site could lead to the development of antivirals which disrupt this interaction and affect capsid assembly.

scholarly journals Receptor flexibility in molecular cross-docking

2016 ◽  
Author(s):  
Lucia Sessa ◽  
Luigi Di BIasi ◽  
Rosaura Parisi ◽  
Simona Concilio ◽  
Stefano Piotto
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Ligand Binding ◽  
Computational Cost ◽  
Md Simulations ◽  
Binding Pocket ◽  
Receptor Flexibility ◽  
Cross Docking ◽  
Internal Cavities ◽  
The Cross

Motivation Molecular docking is an efficient method to predict the conformations adopted by the ligand within the target binding site. Usually, standard docking protocol involves only one structure to represent the receptor, overlooking the changes in the binding pocket geometry induced by ligand binding. In our previous work, we observed that different conformations of the same target show different volume and shape of the internal cavities (Sessa et al., 2016). Different ligands may stabilize different receptor conformations with different internal cavities. Consequently, the crystallographic data represent the adaptation of a protein to a particular ligand. Cross-docking is a validation procedure consisting in docking a series of ligands into different conformation of the same receptor. Since the structures of the same receptor can be rather different, the cross-docking analyses are typically very poor. In these cases the internal cavity of the buried binding pocket does not have space enough to accommodate all ligands and this can radically affect the outcome and alter the cross-docking results. The changes of the cavity volume might explain the failure of traditional docking method and support the hypothesis that a single representative structure for the receptor is not enough. Keeping target proteins flexible during the docking has a high computational cost. To overcome this limit, our docking strategy is to represent receptor flexibility through an inexpensive method that generates a series of target structures. Starting from a known target structure, we used the molecular dynamics (MD) simulations to explore the conformational changes induced by ligand binding and to collect several snapshots of receptor structures to perform the cross-docking studies. To validate the accuracy of our flexible protocol in docking, we used a set of 10 crystallographic conformations of Androgen Receptor with the same target but with a different ligand. We performed two parallel experiments of docking, one with a rigid protein target and one considering flexible receptor structures. In addition, we compared the results for both experiments in the re-docking and in the cross-docking analysis. Methods Ten receptor structures complexed with a ligand were extracted from the X-ray structures in the PDB database (Berman et al., 2000). Several conformations for each receptor were selected from the molecular dynamics simulations (MD) at regular time intervals (each 500 ps). The MD simulations were performed with the software YASARA Structure 16.2.14 (Krieger & Vriend, 2014) using AMBER14 as force field. The molecular docking simulations were performed using VINA provided in the YASARA package. "Abstract truncated at 3,000 characters - the full version is available in the pdf file"

scholarly journals Receptor flexibility in molecular cross-docking

2016 ◽  
Author(s):  
Lucia Sessa ◽  
Luigi Di BIasi ◽  
Rosaura Parisi ◽  
Simona Concilio ◽  
Stefano Piotto
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Ligand Binding ◽  
Computational Cost ◽  
Md Simulations ◽  
Binding Pocket ◽  
Receptor Flexibility ◽  
Cross Docking ◽  
Internal Cavities ◽  
The Cross

Motivation Molecular docking is an efficient method to predict the conformations adopted by the ligand within the target binding site. Usually, standard docking protocol involves only one structure to represent the receptor, overlooking the changes in the binding pocket geometry induced by ligand binding. In our previous work, we observed that different conformations of the same target show different volume and shape of the internal cavities (Sessa et al., 2016). Different ligands may stabilize different receptor conformations with different internal cavities. Consequently, the crystallographic data represent the adaptation of a protein to a particular ligand. Cross-docking is a validation procedure consisting in docking a series of ligands into different conformation of the same receptor. Since the structures of the same receptor can be rather different, the cross-docking analyses are typically very poor. In these cases the internal cavity of the buried binding pocket does not have space enough to accommodate all ligands and this can radically affect the outcome and alter the cross-docking results. The changes of the cavity volume might explain the failure of traditional docking method and support the hypothesis that a single representative structure for the receptor is not enough. Keeping target proteins flexible during the docking has a high computational cost. To overcome this limit, our docking strategy is to represent receptor flexibility through an inexpensive method that generates a series of target structures. Starting from a known target structure, we used the molecular dynamics (MD) simulations to explore the conformational changes induced by ligand binding and to collect several snapshots of receptor structures to perform the cross-docking studies. To validate the accuracy of our flexible protocol in docking, we used a set of 10 crystallographic conformations of Androgen Receptor with the same target but with a different ligand. We performed two parallel experiments of docking, one with a rigid protein target and one considering flexible receptor structures. In addition, we compared the results for both experiments in the re-docking and in the cross-docking analysis. Methods Ten receptor structures complexed with a ligand were extracted from the X-ray structures in the PDB database (Berman et al., 2000). Several conformations for each receptor were selected from the molecular dynamics simulations (MD) at regular time intervals (each 500 ps). The MD simulations were performed with the software YASARA Structure 16.2.14 (Krieger & Vriend, 2014) using AMBER14 as force field. The molecular docking simulations were performed using VINA provided in the YASARA package. "Abstract truncated at 3,000 characters - the full version is available in the pdf file"

scholarly journals Bridging Carotenoid-to-Bacteriochlorophyll Energy Transfer of Purple Bacteria LH2 With Temperature Variations: Insights From Conformational Changes

2021 ◽  
Vol 9 ◽  
Author(s):  
Ruichao Mao ◽  
Xiaocong Wang ◽  
Jun Gao
Keyword(s):  
Molecular Dynamics ◽  
Quantum Mechanics ◽  
Conformational Changes ◽  
Purple Bacteria ◽  
Md Simulations ◽  
Temperature Variations ◽  
Energy Transfers ◽  
N Terminus ◽  
Higher Temperature ◽  
Coupling Strengths

Photosynthesis is a key process for converting light energy into chemical energy and providing food for lives on Earth. Understanding the mechanism for the energy transfers could provide insights into regulating energy transfers in photosynthesis and designing artificial photosynthesis systems. Many efforts have been devoted to exploring the mechanism of temperature variations affecting the excitonic properties of LH2. In this study, we performed all-atom molecular dynamics (MD) simulations and quantum mechanics calculations for LH2 complex from purple bacteria along with its membrane environment under three typical temperatures: 270, 300, and 330 K. The structural analysis from validated MD simulations showed that the higher temperature impaired interactions at N-terminus of both α and β polypeptide helices and led to the dissociation of this hetero polypeptide dimer. Rhodopin-β-D-glucosides (RG1) moved centripetally with α polypeptide helices when temperature increased and enlarged their distances with bacteriochlorophylls molecules that have the absorption peak at 850 nm (B850), which resulted in reducing the coupling strengths between RG1 and B850 molecules. The present study reported a cascading mechanism for temperature regulating the energy transfers in LH2 of purple bacteria.

Three Major Phosphoacceptor Sites in HIV-1 Capsid Protein Enhances its Structural Stability and Resistance Against the Inhibitor: Explication Through Molecular Dynamics Simulation, Molecular Docking and DFT Analysis

2020 ◽  
Vol 23 (1) ◽  
pp. 41-54 ◽  
Author(s):  
Nouman Rasool ◽  
Waqar Hussain
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Capsid Protein ◽  
Structural Stability ◽  
Md Simulations ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Maximum Stability ◽  
The Stability ◽  
Hiv 1

Background: Human Immunodeficiency Virus 1 (HIV-1) is a lentivirus, which causes various HIV-associated infections. The HIV-1 core dissociation is essential for viral cDNA synthesis and phosphorylation of HIV-1 capsid protein (HIV-1 CA) plays an important role in it. Objective: The aim of this study was to explicate the role of three phosphoserine sites i.e. Ser109, Ser149 and Ser178 in the structural stability of HIV-1 CA, and it’s binding with GS-CA1, a novel potent inhibitor. Method: Eight complexes were analyzed and Molecular Dynamics (MD) simulations were performed to observe the stability of HIV-1 CA in the presence and absence of phosphorylation of serine residues at four different temperatures i.e. 300K, 325K, 340K and 350K, along with molecular docking and DFT analysis. Results: The structures showed maximum stability in the presence of phosphorylated serine residue. However, GS-CA1 docked most strongly with the native structure of HIV-1 CA i.e. binding affinity was -8.5 kcal/mol (Ki = 0.579 µM). Conclusion: These results suggest that the phosphorylation of these three serine residues weakens the binding of GS-CA1 with CA and casts derogatory effect on inhibition potential of this inhibitor, but it supports the stability of HIV-1 CA structure that can enhance regulation and replication of HIV-1 in host cells.

scholarly journals CpG Dinucleotides Inhibit HIV-1 Replication through Zinc Finger Antiviral Protein (ZAP)-Dependent and -Independent Mechanisms

2019 ◽  
Vol 94 (6) ◽  
Author(s):  
Mattia Ficarelli ◽  
Irati Antzin-Anduetza ◽  
Rupert Hugh-White ◽  
Andrew E. Firth ◽  
Helin Sertkaya ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Zinc Finger ◽  
Splice Site ◽  
Viral Genome ◽  
Rna Virus ◽  
Antiviral Protein ◽  
Cpg Dinucleotides ◽  
Viral Genomes ◽  
Hiv 1 ◽  
Cpg Suppression

ABSTRACT CpG dinucleotides are suppressed in the genomes of many vertebrate RNA viruses, including HIV-1. The cellular antiviral protein ZAP (zinc finger antiviral protein) binds CpGs and inhibits HIV-1 replication when CpGs are introduced into the viral genome. However, it is not known if ZAP-mediated restriction is the only mechanism driving CpG suppression. To determine how CpG dinucleotides affect HIV-1 replication, we increased their abundance in multiple regions of the viral genome and analyzed the effect on RNA expression, protein abundance, and infectious-virus production. We found that the antiviral effect of CpGs was not correlated with their abundance. Interestingly, CpGs inserted into some regions of the genome sensitize the virus to ZAP antiviral activity more efficiently than insertions into other regions, and this sensitivity can be modulated by interferon treatment or ZAP overexpression. Furthermore, the sensitivity of the virus to endogenous ZAP was correlated with its sensitivity to the ZAP cofactor KHNYN. Finally, we show that CpGs in some contexts can also inhibit HIV-1 replication by ZAP-independent mechanisms, and one of these is the activation of a cryptic splice site at the expense of a canonical splice site. Overall, we show that the location and sequence context of the CpG in the viral genome determines its antiviral activity. IMPORTANCE Some RNA virus genomes are suppressed in the nucleotide combination of a cytosine followed by a guanosine (CpG), indicating that they are detrimental to the virus. The antiviral protein ZAP binds viral RNA containing CpGs and prevents the virus from multiplying. However, it remains unknown how the number and position of CpGs in viral genomes affect restriction by ZAP and whether CpGs have other antiviral mechanisms. Importantly, manipulating the CpG content in viral genomes could help create new vaccines. HIV-1 shows marked CpG suppression, and by introducing CpGs into its genome, we show that ZAP efficiently targets a specific region of the viral genome, that the number of CpGs does not predict the magnitude of antiviral activity, and that CpGs can inhibit HIV-1 gene expression through a ZAP-independent mechanism. Overall, the position of CpGs in the HIV-1 genome determines the magnitude and mechanism through which they inhibit the virus.

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