Multiscale Simulation, Modelling and Design

Energetic Fingerprinting of Ligand Binding to Paralogous Proteins: The Case of the Apoptotic Pathway

Published date : 24 Dec 2018

Networks of biological molecules are key to cellular function, governing processes ranging from signal cascade propagation to metabolic pathway regulation. Genetic duplication processes give rise to sets of regulatory proteins that have evolved from a common ancestor, leading to interactomes whose dysregulation is often associated with disease. A better understanding of the determinants of specificity at 21 interfaces shared by functionally related proteins is crucial to the rational design of novel pharmacotherapeutic agents.

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Journal Paper
journal
Journal of Chemical Inofrmation and Modeling, 2018 Dec 24. doi: 10.1021/acs.jcim.8b00765
Impact Factor
3.804

Engineering an Osmosensor by Pivotal Histidine Positioning within Disordered Helices

Published date : 29 Nov 2018

Histidine kinases (HKs) funnel diverse environmental stimuli into a single autophosphorylation event at a conserved histidine residue. The HK EnvZ is a global sensor of osmolality and cellular acid pH. In previous studies, we discovered that osmosensing in EnvZ was mediated through osmolyte-induced stabilization of the partially disordered helical backbone spanning the conserved histidine autophosphorylation site (His243).

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Journal Paper
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Structure, 27, 1-13, Feb 5, doi: 10.1016/j.str.2018.10.012
Impact Factor
4.907

Mechanism of Enhanced Immature Dengue Virus Attachment to Endosomal Membrane Induced by prM Antibody

Published date : 21 Nov 2018

Dengue virus (DENV) particles are released from cells in different maturation states. Fully immature DENV (immDENV) is generally non-infectious, but can become infectious when complexed with anti-precursor membrane (prM) protein antibodies. It is unknown how anti-prM antibody-coated particles can undergo membrane fusion since the prM caps the envelope (E) protein fusion loop. Here, we determined cryoelectron microscopy (cryo-EM) maps of the immDENV:anti-prM complex at different pH values, mimicking the extracellular (pH 8.0) or endosomal (pH 5.0) environments.

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Journal Paper
journal
Structure 27, 1-15, Feb 5, 2019, doi: 10.1016/j.str.2018.10.009
Impact Factor
4.907

Single-molecule studies of flavivirus envelope dynamics: Experiment and computation

Published date : 14 Sep 2018

Flaviviruses are simple enveloped viruses exhibiting complex structural and functional heterogeneities. Decades of research have provided crucial basic insights, antiviral medication and moderately successful gene therapy trials. The most infectious particle is, however, not always the most abundant one in a population, questioning the utility of classic ensemble-averaging virology approaches. Indeed, viral replication is often not particularly efficient, prone to errors or containing parallel routes.

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Journal Paper
journal
Progress in Biophysics and Molecular Biology, 2018, Sep 14, doi: 10.1016/j.pbiomolbio.2018.09.001
Impact Factor
3.427

Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides

Published date : 17 Aug 2018

Thrombin-derived C-terminal peptides (TCPs) of about 2 kDa are present in wounds, where they exert anti-endotoxic functions. Employing a combination of nuclear magnetic resonance spectroscopy (NMR), biophysical, mass spectrometry and cellular studies combined with in silico multiscale modelling, we here determine the bound conformation of HVF18 (HVFRLKKWIQKVIDQFGE), a TCP generated by neutrophil elastase, in complex with bacterial lipopolysaccharide (LPS) and define a previously undisclosed interaction between TCPs and human CD14.

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Journal Paper
journal
Nature Communications, 2018 Jul 17;9(1):2762. doi: 10.1038/s41467-018-05242-0
Impact Factor
12.353

Single mutations in the ε subunit from thermophilic Bacillus PS3 generate a high binding affinity site for ATP

Published date : 02 Aug 2018

The ε subunit from ATP synthases acts as an ATP sensor in the bacterial cell to prevent ATP hydrolysis and thus the waste of ATP under conditions of low ATP concentration. However, the ATP binding affinities from various bacterial organisms differ markedly, over several orders of magnitude. For example, the ATP synthases from thermophilic Bacillus PS3 and Escherichia coli exhibit affinities of 4 µM and 22 mM, respectively.

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Journal Paper
journal
PeerJ 2018, Sep 5, doi: 10.7717/peerj.5505
Impact Factor
2.118

Activation of Toll-like receptors nucleates assembly of the MyDDosome signaling hub

Published date : 26 Jun 2018

Infection and tissue damage induces assembly of supramolecular organizing centres (SMOCs)), such as the Toll-like receptor (TLR) MyDDosome, to co-ordinate inflammatory signaling. SMOC assembly is thought to drive digital all-or-none responses, yet TLR activation by diverse microbes induces anything from mild to severe inflammation. Using single-molecule imaging of TLR4-MyDDosome signaling in living macrophages, we find that MyDDosomes assemble within minutes of TLR4 stimulation.

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Journal Paper
journal
eLife, 2018 Jan 24;7. pii: e31377. doi: 10.7554/eLife.31377
Impact Factor
7.616

A Funneled Conformational Landscape Governs Flavivirus Fusion Peptide Interaction with Lipid Membranes

Published date : 06 Jun 2018

During host cell infection by flaviviruses such as dengue and Zika, acidic pH within the endosome triggers a conformational change in the envelope protein on the outer surface of the virion. This results in exposure of the ∼15 residue fusion peptide (FP) region, freeing it to induce fusion between the viral and endosomal membranes. A better understanding of the conformational dynamics of the FP in the presence of membranes, and the basis for its selectivity for anionic lipid species present within the endosome, would facilitate its therapeutic targeting with antiviral drugs and antibodies.

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Journal Paper
journal
Journal of Chemical Theory and Computation, 2018 Jul 10;14(7):3920-3932. doi: 10.1021/acs.jctc.8b00438
Impact Factor
5.399

Influence of pH on the activity of thrombin-derived antimicrobial peptides

Published date : 06 Jun 2018

The wound environment is characterized by physiological pH changes. Proteolysis of thrombin by wound-derived proteases, such as neutrophil elastase, generates antimicrobial thrombin-derived C-terminal peptides (TCPs), such as HVF18 (HVFRLKKWIQKVIDQFGE). Presence of such TCPs in human wound fluids in vivo, as well as the occurrence of an evolutionarily conserved His residue in the primary amino acid sequence of TCPs, prompted us to investigate the pH-dependent antibacterial action of HVF18, as well as of the prototypic GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE).

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Journal Paper
journal
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2018 Jun 6, doi: 10.1016/j.bbamem.2018.06.002
Impact Factor
3.438

The architecture of the OmpC-MlaA complex sheds light on the maintenance of outer membrane lipid asymmetry in Escherichia coli

Published date : 30 May 2018

A distinctive feature of the Gram-negative bacterial cell envelope is the asymmetric outer membrane (OM), where lipopolysaccharides and phospholipids (PLs) reside in the outer and inner leaflets, respectively. This unique lipid asymmetry renders the OM impermeable to external insults, including antibiotics and bile salts. In Escherichia coli, the complex comprising osmoporin OmpC and the OM lipoprotein MlaA is believed to maintain lipid asymmetry by removing mislocalized PLs from the outer leaflet of the OM. How this complex performs this function is unknown.

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Journal Paper
journal
The Journal of Biological Chemistry, 2018 Jul 20;293(29):11325-11340. doi: 10.1074/jbc.RA118.002441
Impact Factor
4.010