Multiscale Simulation

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

Facile saccharide-free mimetics that recapitulate key features of glycosaminoglycan sulfation patterns

Published date : 24 Aug 2018

Controlling glycosaminoglycan (GAG) activity to exploit its immense potential in biology ultimately requires facile manipulation of sulfation patterns associated with GAGs. However, satisfying this requirement in full remains challenging, given that synthesis of GAGs is technically arduous while convenient GAG mimetics often produce sulfation patterns that are uncharacteristic of GAGs. To overcome this, we develop saccharide-free polyproline-based GAG mimetics (PGMs) that can be facilely assembled via amide coupling chemistry.

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Journal Paper
journal
Chemical Science, 2018, 9, 7940-7947, doi: 10.1039/C8SC02303D
Impact Factor
4.907

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

Dynamics of crowded vesicles: local and global responses to membrane composition

Published date : 16 Jun 2016

The bacterial cell envelope is composed of a mixture of different lipids and proteins, making it an inherently complex organelle. The interactions between integral membrane proteins and lipids are crucial for their respective spatial localization within bacterial cells. We have employed microsecond timescale coarse-grained molecular dynamics simulations of vesicles of varying sizes and with a range of protein and lipid compositions, and used novel approaches to measure both local and global system dynamics, the latter based on spherical harmonics analysis.

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Journal Paper
journal
PLOS One, June 16, 2016, DOI:10.1371/journal.pone.0156963
Impact Factor
3.057