Atomistic Simulations and Design in Biology

Kinetic and thermodynamic effects of phosphorylation on p53 binding to MDM2

Published date : 24 Jan 2019

p53 is frequently mutated in human cancers. Its levels are tightly regulated by the E3 ubiquitin ligase MDM2. The complex between MDM2 and p53 is largely formed by the interaction between the N-terminal domain of MDM2 and the N-terminal transactivation (TA) domain of p53 (residues 15-29). We investigated the kinetic and thermodynamic basis of the MDM2/p53 interaction by using wild-type and mutant variants of the TA domain. We focus on the effects of phosphorylation at positions Thr18 and Ser20 including their substitution with phosphomimetics.

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Journal Paper
journal
Scientific Reports 9, Article no: 693 (2019). doi: 10.1038/s41598-018-36589-5
Impact Factor
4.122

Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket

Published date : 15 Jan 2019

The DNA binding domain (DBD) of the tumor suppressor p53 is the site of several oncogenic mutations. A subset of these mutations lowers the unfolding temperature of the DBD. Unfolding leads to the exposure of a hydrophobic β-strand and nucleates aggregation which results in pathologies through loss of function and dominant negative/gain of function effects.

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Journal Paper
journal
Nuclei Acids Research, 2019, doi: 10.1093/nar/gky1314
Impact Factor
11.561

Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein

Published date : 07 Jan 2019

Stapled-peptides have emerged as an exciting class of molecules which can modulate protein–protein interactions. We have used a structure-guided approach to rationally develop a set of hydrocarbon stapled-peptides with high binding affinities and residence times against the oncogenic eukaryotic translation initiation factor 4E (eIF4E) protein. Crystal structures of these peptides in complex with eIF4E show that they form specific interactions with a region on the protein-binding interface of eIF4E which is distinct from the other well-established canonical interactions.

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Journal Paper
journal
Chemical Science, 2019, doi: 10.1039/C8SC03759K
Impact Factor
9.063

Effects of Single Nucleotide Polymorphisms on the Binding of Afatinib to EGFR: A Potential Patient Stratification Factor Revealed by Modeling Studies

Published date : 27 Nov 2018

The anticancer drug afatinib has been found to be more effective at inhibiting the oncogenic EGFR mutant exon 19 deletion (19del) over the oncogenic EGFR mutant L858R. The underlying mechanism has been hypothesized to result from differences in structural constraints introduced by the mutations and stabilizing interactions afforded by a buried water molecule in 19del (Kannan S. et al. Scientific Reports 2017, 7: 1540). The COSMIC cancer database is mined for EGFR sequences to discover that several mutations in the form of Single Nucleotide Polymorphisms (SNPs) line this hydration cavity.

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The anticancer drug afatinib has been found to be more effective at inhibiting the oncogenic EGFR mutant exon 19 deletion (19del) over the oncogenic EGFR mutant L858R. The underlying mechanism has been hypothesized to result from differences in structural constraints introduced by the mutations and stabilizing interactions afforded by a buried water molecule in 19del (Kannan S. et al. Scientific Reports 2017, 7: 1540). The COSMIC cancer database is mined for EGFR sequences to discover that several mutations in the form of Single Nucleotide Polymorphisms (SNPs) line this hydration cavity. In this work, the effects of these SNPs on the affinity of afatinib for EGFRWT and oncogenic mutants EGFRL858R and EGFR19del were studied using Free Energy Perturbation and Thermodynamic Integration calculations. The simulations reveal that several SNPs have significant effects on the affinity of afatinib for the mutant EGFRs carrying the SNPs and may thus have clinical implications relating to emergence of resistance to afatinib, thus potentially impacting the choice of EGFR inhibitors in the clinic.
journal
Journal of Chemical Information and Modeling, 2018 Nov 27. doi: 10.1021/acs.jcim.8b00491
Impact Factor
3.804

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

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.

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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.

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

Reactive Metabolite-induced Protein Glutathionylation: a Potentially Novel Mechanism Underlying Acetaminophen Hepatotoxicity

Published date : 13 Jul 2018

Although covalent protein binding is established as the pivotal event underpinning acetaminophen (APAP) toxicity, its mechanistic details remain unclear. In this study, we demonstrated that APAP induces widespread protein glutathionylation in a time-, dose- and bioactivation-dependent manner in HepaRG cells.

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Journal Paper
journal
Molecular & Cellular Proteomics, 2018, Jul 13, doi: 10.1074/mcp.RA118.000875
Impact Factor
5.232

Homologous Lympho-Epithelial Kazal-type Inhibitor Domains Delay Blood Coagulation by Inhibiting Factor X and XI with Differential Specificity

Published date : 12 Jul 2018

Despite being initially identified in the blood filtrate, LEKTI is a 15-domain Kazal-type inhibitor mostly known in the regulation of skin desquamation. In the current study, screening of serine proteases in blood coagulation cascade showed that LEKTI domain 4 has inhibitory activity toward only FXIa, whereas LEKTI domain 6 inhibits both FXIa and FXaB (bovine FXa). Nuclear magnetic resonance structural and dynamic experiments plus molecular dynamics simulation revealed that LEKTI domain 4 has enhanced backbone flexibility at the reactive-site loop.

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Journal Paper
journal
Structure, 26, Pg 1178-1186, Sept 4, 2018, doi: 10.1016/j.str.2018.05.018, PMID: 30017565
Impact Factor
4.907

Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide

Published date : 05 Jul 2018

Sal-like 4 (SALL4) is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in hepatocellular carcinoma, a malignancy with no effective treatment. In cancer cells, SALL4 associates with nucleosome remodeling deacetylase (NuRD) to silence tumor-suppressor genes, such as PTEN.

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Journal Paper
journal
Proceedings of the National Academy of Sciences of the United States of America (PNAS), July 24, 2018, Vol. 115, no. 30, Pg E7119-E7128, doi: 10.1073/pnas.1801253115
Impact Factor
9.504