Mechanisms of allostery at the viral surface through the eyes of molecular simulation.

The outermost surface layer of any virus is formed by either a capsid shell or envelope. Such layers have traditionally been thought of as immovable structures, but it is becoming apparent that they cannot be viewed exclusively as static architectures protecting the viral genome. A limited number of proteins on the virion surface must perform a multitude of functions in order to orchestrate the viral life cycle, and allostery can regulate their structures at multiple levels of organization, spanning individual molecules, protomers, large oligomeric assemblies, or entire viral surfaces.

The ganglioside GM1a functions as a coreceptor/attachment factor for dengue virus during infection.

Dengue virus (DENV) is a flavivirus causing an estimated 390 million infections per year around the world. Despite the immense global health and economic impact of this virus, its true receptor(s) for internalization into live cells has not yet been identified, and no successful antivirals or treatments have been isolated to this date. This study aims to improve our understanding of virus entry routes by exploring the sialic acid-based cell surface molecule GM1a and its role in DENV infection.

Development of a novel peptide aptamer that interacts with the eIF4E capped-mRNA binding site using peptide epitope linker evolution (PELE).

Identifying new binding sites and poses that modify biological function are an important step towards drug discovery. We have identified a novel disulphide constrained peptide that interacts with the cap-binding site of eIF4E, an attractive therapeutic target that is commonly overexpressed in many cancers and plays a significant role in initiating a cancer specific protein synthesis program though binding the 5'cap (7'methyl-guanoisine) moiety found on mammalian mRNAs. The use of disulphide constrained peptides to explore intracellular biological targets is limited by their lack of cell permeability and the instability of the disulphide bond in the reducing environment of the cell, loss of which results in abrogation of binding.

Motional clustering in supra-τ conformational exchange influences NOE cross-relaxation rate.

Biomolecular spin relaxation processes, such as the NOE, are commonly modeled by rotational τ-tumbling combined with fast motions on the sub-τ timescale. Motions on the supra-τ timescale, in contrast, are considered to be completely decorrelated to the molecular tumbling and therefore invisible. Here, we show how supra-τ dynamics can nonetheless influence the NOE build-up between methyl groups.

How well does molecular simulation reproduce environment-specific conformations of the intrinsically disordered peptides PLP, TP2 and ONEG?

Understanding the conformational ensembles of intrinsically disordered proteins and peptides (IDPs) in their various biological environments is essential for understanding their mechanisms and functional roles in the proteome, leading to a greater knowledge of, and potential treatments for, a broad range of diseases. To determine whether molecular simulation is able to generate accurate conformational ensembles of IDPs, we explore the structural landscape of the PLP peptide (an intrinsically disordered region of the proteolipid membrane protein) in aqueous and membrane-mimicking solvents, using replica exchange with solute scaling (REST2), and examine the ability of four force fields (ff14SB, ff14IDPSFF, CHARMM36 and CHARMM36m) to reproduce literature circular dichroism (CD) data. Results from variable temperature (VT) H and Rotating frame Overhauser Effect SpectroscopY (ROESY) nuclear magnetic resonance (NMR) experiments are also presented and are consistent with the structural observations obtained from the simulations and CD.

Evaluation of Host Defense Peptide (CaD23)-Antibiotic Interaction and Mechanism of Action: Insights From Experimental and Molecular Dynamics Simulations Studies.

Host defense peptides (HDPs) have the potential to provide a novel solution to antimicrobial resistance (AMR) in view of their unique and broad-spectrum antimicrobial activities. We had recently developed a novel hybrid HDP based on LL-37 and human beta-defensin-2, named CaD23, which was shown to exhibit good antimicrobial efficacy against in a bacterial keratitis murine model. This study aimed to examine the potential CaD23-antibiotic synergism and the secondary structure and underlying mechanism of action of CaD23.

The impact of Gag non-cleavage site mutations on HIV-1 viral fitness from integrative modelling and simulations.

The high mutation rate in retroviruses is one of the leading causes of drug resistance. In human immunodeficiency virus type-1 (HIV-1), synergistic mutations in its protease and the protease substrate - the Group-specific antigen (Gag) polyprotein - work together to confer drug resistance against protease inhibitors and compensate the mutations affecting viral fitness. Some Gag mutations can restore Gag-protease binding, yet most Gag-protease correlated mutations occur outside of the Gag cleavage site.

Not all therapeutic antibody isotypes are equal: the case of IgM IgG in Pertuzumab and Trastuzumab.

The therapeutic potential of immunoglobulin M (IgM) is of considerable interest in immunotherapy due to its complement-activating and cell-agglutinating abilities. Pertuzumab and Trastuzumab are monoclonal antibodies used to treat human epidermal growth factor receptor 2 (HER2)-positive breast cancer but exhibit significantly different binding affinities as IgM when compared to its IgG isotype. Using integrative multiscale modelling and simulations of complete antibody assemblies, we show that Pertuzumab IgM is able to utilize all of its V-regions to bind multiple HER2 receptors simultaneously, while similar binding in Trastuzumab IgM is prohibited by steric clashes caused by the large globular domain of HER2.

Author Correction: Structural basis for delta cell paracrine regulation in pancreatic islets.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Structural basis for delta cell paracrine regulation in pancreatic islets.

Little is known about the role of islet delta cells in regulating blood glucose homeostasis in vivo. Delta cells are important paracrine regulators of beta cell and alpha cell secretory activity, however the structural basis underlying this regulation has yet to be determined. Most delta cells are elongated and have a well-defined cell soma and a filopodia-like structure.

Small Molecules Targeting the Inactive Form of the Mnk1/2 Kinases.

Overexpression of the eukaryotic initiation factor 4E (eIF4E) is linked to a variety of cancers. Both mitogen-activated protein kinases-interacting kinases 1 and 2 (Mnk1/2) activate the oncogene eIF4E through posttranslational modification (phosphorylating it at the conserved Ser209). Inhibition of Mnk prevents eIF4E phosphorylation, making the Mnk-eIF4E axis a potential therapeutic target for oncology.

Comparison of Charge Derivation Methods Applied to Amino Acid Parameterization.

When using non-natural amino acids in computational simulations of proteins, it is necessary to ensure appropriate parameterization of the new amino acids toward the creation of appropriate input files. In particular, the charges on the atoms may have to be derived de novo and ad hoc for the new species. As there are many variables in the charge derivation process, an investigation was devised to compare different approaches and determine their effect on simulations.

A Spring-Loaded Mechanism Governs the Clamp-like Dynamics of the Skp Chaperone.

The trimeric periplasmic holdase chaperone Skp binds and stabilizes unfolded outer membrane proteins (OMPs) as part of bacterial OMP biogenesis. Skp binds client proteins in its central cavity, thereby reducing its backbone dynamics, but the molecular mechanisms that govern Skp dynamics and adaptation to differently sized clients remains unknown. Here, we employ a combination of microsecond timescale molecular dynamics simulation, small-angle X-ray scattering, and nuclear magnetic resonance spectroscopy to reveal that Skp is remarkably flexible, and features a molecular spring-loaded mechanism in its "tentacle" arms that enables switching between two distinct conformations on sub-millisecond timescales.

Corrigendum to "Discovery of novel interacting partners of PSMD9, a proteasomal chaperone: Role of an Atypical and versatile PDZ-domain motif interaction and identification of putative functional modules" [FEBS Open Bio 4 (2014) 571-583].

[This corrects the article DOI: 10.1016/j.fob.

The role of protein-protein interactions in Toll-like receptor function.

As part of the innate immune system, the Toll-like receptors (TLRs) represent key players in the first line of defense against invading foreign pathogens, and are also major targets for therapeutic immunomodulation. TLRs are type I transmembrane proteins composed of an ectodomain responsible for ligand binding, a single-pass transmembrane domain, and a cytoplasmic Toll/Interleukin-1 receptor (TIR) signaling domain. The ectodomains of TLRs are specialized for recognizing a wide variety of pathogen-associated molecular patterns, ranging from lipids and lipopeptides to proteins and nucleic acid fragments.

Aspergillus fumigatus harbouring the sole Y121F mutation shows decreased susceptibility to voriconazole but maintained susceptibility to itraconazole and posaconazole.

Objectives: Voriconazole, itraconazole and posaconazole are members of the azole family and widely used for the treatment of aspergillosis. They act by inhibiting the activity of the fungal Cyp51A enzyme. The emergence of environmental azole-resistant Aspergillus fumigatus strains raises major concerns for human health.

Discovery of novel interacting partners of PSMD9, a proteasomal chaperone: Role of an Atypical and versatile PDZ-domain motif interaction and identification of putative functional modules.

PSMD9 (Proteasome Macropain non-ATPase subunit 9), a proteasomal assembly chaperone, harbors an uncharacterized PDZ-like domain. Here we report the identification of five novel interacting partners of PSMD9 and provide the first glimpse at the structure of the PDZ-domain, including the molecular details of the interaction. We based our strategy on two propositions: (a) proteins with conserved C-termini may share common functions and (b) PDZ domains interact with C-terminal residues of proteins.

Synthetic multivalent antifungal peptides effective against fungi.

Taking advantage of the cluster effect observed in multivalent peptides, this work describes antifungal activity and possible mechanism of action of tetravalent peptide (B4010) which carries 4 copies of the sequence RGRKVVRR through a branched lysine core. B4010 displayed better antifungal properties than natamycin and amphotericin B. The peptide retained significant activity in the presence of monovalent/divalent cations, trypsin and serum and tear fluid.