Atomistic Simulations and Design in Biology

Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53

Murine double minute 4 protein (MDMX) is crucial for the regulation of the tumor suppressor protein p53. Phosphorylation of the N-terminal domain of MDMX is thought to affect its binding with the transactivation domain of p53, thus playing a role in p53 regulation. In this study, the effects of MDMX phosphorylation on the binding of p53 were investigated using molecular dynamics simulations.

type: 
Journal Paper
journal: 
Oncotarget, 2017, Vol. 8, No. 68, Pg 112825-112840, doi.org/10.18632/oncotarget.22829
Url: 
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=22829
Impact Factor: 
5.168
Date of acceptance: 
2017-10-05

Covariant Conservation Laws and the Spin Hall Effect in Dirac-Rashba Systems

We present a theoretical analysis of two-dimensional Dirac-Rashba systems in the presence of disorder and external perturbations. We unveil a set of exact symmetry relations (Ward identities) that impose strong constraints on the spin dynamics of Dirac fermions subject to proximity-induced interactions. This allows us to demonstrate that an arbitrary dilute concentration of scalar impurities results in the total suppression of nonequilibrium spin Hall currents when only Rashba spin-orbit coupling is present.

type: 
Journal Paper
journal: 
Physical Review Letters, Vol. 119, Issue 24, 14 Dec 2017, doi: 10.1103/PhysRevLett.119.246801
Url: 
https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.119.246801
Impact Factor: 
8.462

Structural analysis of protein tyrosine phosphatase 1B reveals potentially druggable allosteric binding sites

Catalytic proteins such as human protein tyrosine phosphatase 1B (PTP1B), with conserved and highly polar active sites, warrant the discovery of druggable non-active sites, such as allosteric sites, and potentially, therapeutic small molecules that can bind to these sites. Catalyzing the dephosphorylation of numerous substrates, PTP1B is physiologically important in intracellular signal transduction pathways in diverse cell types and tissues. Aberrant PTP1B is associated with obesity, diabetes, cancers, and neurodegenerative disorders.

type: 
Journal Paper
journal: 
Proteins: Structure, Function, and Bioinformatics, 13 Dec 2017, doi: 10.1002/prot.25440
pubmed: 
29235148
Url: 
https://www.ncbi.nlm.nih.gov/pubmed/29235148
Impact Factor: 
2.499
Date of acceptance: 
2017-12-27

An Intramolecular Tryptophan-Condensation Approach for Peptide Stapling

Stapled peptides are gaining tremendous interest as next-generation therapeutic agents to target protein-protein interactions. Herein, we report an intramolecular peptide stapling method which links two tryptophan residues at C2 position of the indole moieties via acid-mediated condensation with an aldehyde.

type: 
Journal Paper
journal: 
Organic & Biomolecular Chemistry, 2017, doi: 10.1039/C7OB02667F
Url: 
http://pubs.rsc.org/en/content/articlelanding/2017/ob/c7ob02667f#!divAbstract
Impact Factor: 
3.564
Date of acceptance: 
2017-12-07

Spin-charge conversion in disordered two-dimensional electron gases lacking inversion symmetry

We study the spin-charge conversion mechanisms in a two-dimensional gas of electrons moving in a smooth disorder potential by accounting for both Rashba-type and Mott's skew scattering contributions. We find that the quantum interference effects between spin-flip and skew scattering give rise to anisotropic spin precession scattering (ASP), a direct spin-charge conversion mechanism that was discovered in an earlier study of graphene decorated with adatoms [Huang et al., Phys. Rev. B 94, 085414 (2016)].

type: 
Journal Paper
journal: 
Physical Review B, Vol. 96, 2017, doi: 10.1103/PhysRevB.96.205305
Url: 
https://journals.aps.org/prb/abstract/10.1103/PhysRevB.96.205305
Impact Factor: 
3.836

Characterizing the Conformational Landscape of MDM2-binding p53 peptides using Molecular Dynamics simulations

The conformational landscapes of p53 peptide variants and phage derived peptide (12/1) variants, all known to bind to MDM2, are studied using hamiltonian replica exchange molecular dynamics simulations. Complementing earlier observations, the current study suggests that the p53 peptides largely follow the ‘conformational selection’ paradigm in their recognition of and complexation by MDM2 while the 12/1 peptides likely undergo some element of conformational selection but are mostly driven by ‘binding induced folding’.

type: 
Journal Paper
journal: 
Scientific Reports 7, Article no:15600, 2017, doi:10.1038/s41598-017-15930-4
Url: 
https://www.nature.com/articles/s41598-017-15930-4
Impact Factor: 
4.259
Date of acceptance: 
2017-11-03

Small molecules targeting the inactive form of the Mnk 1/2 kinases

Overexpression of the eukaryotic initiation factor 4E (eIF4E) is linked to a variety of cancers. Both mitogenactivated 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. Recently, the design and synthesis of a series of novel potent compounds inhibiting the Mnk1/2 kinases were carried out in-house.

type: 
Journal Paper
journal: 
ACS Omega 2017, 2, Pg 7881 - 7891, doi: 10.1021/acsomega.7b01403
Date of acceptance: 
2017-10-31

A yeast two-hybrid system for the screening and characterization of small-molecule inhibitors of protein–protein interactions identifies a novel putative Mdm2-binding site in p53

Background: Protein–protein interactions (PPIs) are fundamental to the growth and survival of cells and serve as excellent targets to develop inhibitors of biological processes such as host-pathogen interactions and cancer cell proliferation. However, isolation of PPI inhibitors is extremely challenging. While several in vitro assays to screen for PPI inhibitors are available, they are often expensive, cumbersome, and require large amounts of purified protein. In contrast, limited in vivo assays are available to screen for small-molecule inhibitors of PPI.

type: 
Journal Paper
journal: 
BMC Biology 2017 15:108, doi: 10.1186/s12915-017-0446-7
Url: 
https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-017-0446-7
Impact Factor: 
6.779
Date of acceptance: 
2017-10-19

Optimal Charge-to-Spin Conversion in Graphene on Transition-Metal Dichalcogenides

When graphene is placed on a monolayer of semiconducting transition metal dichalcogenide (TMD) its band structure develops rich spin textures due to proximity spin-orbital effects with interfacial breaking of inversion symmetry. In this work, we show that the characteristic spin winding of low-energy states in graphene on a TMD monolayer enables current-driven spin polarization, a phenomenon known as the inverse spin galvanic effect (ISGE).

type: 
Journal Paper
journal: 
Physical Review Letters, Vol. 114, Issue 119, 10 Nov 2017, doi: 10.1103/PhysRevLett.119.196801
Url: 
https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.119.196801
Impact Factor: 
8.462

A New Generation of Arachidonic Acid Analogues as Potential Neurological Agent Targeting Cytosolic Phospholipase A2

Cytosolic phospholipase A2 (cPLA2) is an enzyme that releases arachidonic acid (AA) for the synthesis of eicosanoids and lysophospholipids which play critical roles in the initiation and modulation of oxidative stress and neuroinflammation. In the central nervous system, cPLA2 activation is implicated in the pathogenesis of various neurodegenerative diseases that involves neuroinflammation, thus making it an important pharmacological target. In this paper, a new class of arachidonic acid (AA) analogues was synthesized and evaluated for their ability to inhibit cPLA2.

type: 
Journal Paper
journal: 
Scientific Reports 7, Article no: 13684, 2017, doi:10.1038/s41598-017-13996-8
Url: 
https://www.nature.com/articles/s41598-017-13996-8
Impact Factor: 
4.259
Date of acceptance: 
2017-10-05
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