Biomolecular Modelling & Design Division

Simple yet functional phosphate-loop proteins

Published date : 30 Nov 2018

Abundant and essential motifs, such as phosphate-binding loops (P-loops), are presumed to be the seeds of modern enzymes. The Walker-A P-loop is absolutely essential in modern NTPase enzymes, in mediating binding, and transfer of the terminal phosphate groups of NTPs. However, NTPase function depends on many additional active-site residues placed throughout the protein’s scaffold. Can motifs such as P-loops confer function in a simpler context?

type
Journal Paper
journal
Proceedings of the National Academy of Sciences of the United States of America, PNAS, doi: 10.1073/pnas.1812400115
Impact Factor
9.504

On the perturbation nature of allostery: sites, mutations, and signal modulation

Published date : 12 Nov 2018

Regardless of the diversity of systems, allosteic signalling is found to be always caused by perturbations. This recurring trait of allostery serves as a foundation for developing different experimental efforts and theoretical models for the studies of allosteric mechanisms. Among computational approaches considered here particular emphasis is given to the structure-based statistical mechanical model of allostery (SBSMMA), which allows one to study the causality and energetics of allosteric communication.

type
Journal Paper
journal
Current Opinion in Structural Biology, Vol. 56, June 2019, Pg 18-27, doi: 10.1016/j.sbi.2018.10.008
Impact Factor
7.179

A dual substrate-accessing mechanism of a major facilitator superfamily protein facilitates lysophospholipid flipping across the cell membrane

Published date : 29 Oct 2018

Lysophospholipid transporter (LplT) is a member of the major facilitator superfamily (MFS) present in many Gram-negative bacteria. LplT catalyzes flipping of lysophospholipids (LPLs) across the bacterial inner membrane, playing an important role in bacterial membrane homeostasis. We previously reported that LplT promotes both uptake of exogenous LPLs and intramembranous LPL flipping across the bilayer.

type
Journal Paper
journal
Journal of Biological Chemistry, 2018, October 29, doi: 10.1074/jbc.RA118.005548
Impact Factor
4.01

AlloMAPS: allosteric mutation analysis and polymorphism of signaling database

Published date : 26 Oct 2018

AlloMAPS database provides data on the causality and energetics of allosteric communication obtained with the structure-based statistical mechanical model of allostery (SBSMMA). The database contains data on allosteric signaling in three sets of proteins and protein chains: (i) 46 proteins with comprehensively annotated functional and allosteric sites; (ii) 1908 protein chains from PDBselect set of chains with low (<25%) sequence identity; (iii) 33 proteins with more than 50 known pathological SNPs in each molecule.

type
Journal Paper
journal
Nucleic Acis Research, 2018, Oct 26, doi:10.1093/nar/gky1028
Impact Factor
11.561

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.

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

Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases

Published date : 14 Sep 2018

The regulation of apoptosis is a tightly-coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted.

type
Journal Paper
journal
Proteins: Structure, Function and Bioinformatics, 2018 Sep 8. doi: 10.1002/prot.25601
Impact Factor
2.274

Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition

Published date : 13 Sep 2018

The signaling of prostaglandin D 2 (PGD 2) through G-protein-coupled receptor (GPCR) CRTH2 is a major pathway in type 2 inflammation. Compelling evidence suggests the therapeutic benefits of blocking CRTH2 signaling in many inflammatory disorders. Currently, a number of CRTH2 antagonists are under clinical investigation, and one compound, fevipiprant, has advanced to phase 3 clinical trials for asthma. Here, we present the crystal structures of human CRTH2 with two antagonists, fevipiprant and CAY10471.

type
Journal Paper
journal
Molecular Cell, 2018, doi: 10.1016/j.molcel.2018.08.009
Impact Factor
14.428

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.

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

Conformational Transitions of Melittin between Aqueous and Lipid Phases: Comparison of Simulations with Experiments

Published date : 16 Aug 2018

Peptides are promising drug candidates with advantageous therapeutic properties. However, their inherent flexibility makes the development of structure−activity relationships difficult. Molecular dynamics simulations have been widely used to study peptide conformations, but they are limited by force field parameters.

type
Journal Paper
journal
The Journal of Physical Chemistry B, 2018, doi: 10.1021/acs.jpcb.8b06781
Impact Factor
3.146

Ultra-High Signal Detection of Human Embryonic Stem Cells Driven by Two-Dimensional Materials

Published date : 08 Aug 2018

We observed a unique bioelectric signal of human embryonic stem cells using direct current−voltage measurements facilitated by few-layered 2DMoS2 sheets. A 1.828 mA cell signal was achieved (2 orders of magnitude higher than previous electrical-based detection methods) as well as multiple cell reading cycles demonstrating I ∼ 1.9 mA. Native stem cell proliferation, viability, and pluripotency were preserved. Molecular dynamics simulations elucidated the origin of the 2D-MoS2 sheet-assisted increase in current flow.

type
Journal Paper
journal
ACS Applied Bio Materials, 2018, 1, Pg 210-215, doi: 10.1021/acsabm.8b00085.