Salomé Llabrés Prat

Salomé Llabrés Prat

Juan de la Cierva Researcher at the CBCG and CBDD groups at University of Barcelona.

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My postdoctoral work is finally published in Chemical Science.

less than 1 minute read

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My postdoctoral work on the selectivity of a drug-like small molecules on the oncoprotein MDM2 is finally out in Chemical Science. While I was a PDRA at the group of Dr Julien Michel at the University of Edinburgh, we explored the molecular determinants that guide the binding of Nutlin-3a and AMG-7209 to MDM2, which involves the disorder-to-order transition of the intrinsically disordered N-terminal region of MDM2. Moreover, we developed a protocol able to accurately estimate the binding affinities of these ligands using complete thermodynamic analysis that featured adaptive absolute alchemical free energy of binding calculations with enhanced-sampling molecular dynamics simulations.

Best Practice Guide for Biomolecular QM/MM simulations with CP2K

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As part of my work in the BioExcel-2 project at the EPCC, I co-wrote a best practice guide on how to perform QM/MM simulations of biomolecules using CP2K. We provided an overview of the main steps in setting up and running a QM/MM simulation in CP2K. We cover steps starting from preparing your system to running a production QM/MM run. This BPG is designed to be read from the point of view of beginner users.

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publications

Exploration of Forbidden Povarov Processes as a Source of Unexpected Reactivity: A Multicomponent Mannich–Ritter Transformation

Published in Angewandte Chemie International Edition, 2012

The use of geometrically or electronically restricted imines for Povarov‐type processes does not afford the anti‐Bredt tetrahydroquinolines, but leads instead to highly functionalized structures through novel reaction pathways (see picture; LA=Lewis acid). The exploration of “forbidden” routes constitutes a valuable approach in the search for new multicomponent reactions.

Recommended citation: Preciado S., Vicente-García E., Llabrés S., Luque FJ. and Lavilla R. (2012) Angewandte Chemie International Edition. 51, 6874–6877. https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201202927

Evolution of a Multicomponent System: Computational and Mechanistic Studies on the Chemo‐and Stereoselectivity of a Divergent Process

Published in Chemistry–A European Journal, 2013

The evolution of a ternary molecular system (imine, diene and nitrile) is analyzed to disclose the pathways leading to a divergent synthetic outcome: an imino‐Diels–Alder adduct as the major product and a minor Mannich–Ritter‐amidine product.

Recommended citation: Llabrés S., Vicente-García E., Preciado S., Guiu C., Pouplana R., Lavilla R. and Luque FJ. (2013). Chemistry: European Journal. 2013, 40, 13555-13361 https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/chem.201302072

Molecular basis of the selective binding of MDMA enantiomers to the alpha4beta2 nicotinic receptor subtype: Synthesis, pharmacological evaluation and mechanistic studies

Published in European Journal of Medicinal Chemistry, 2014

The alpha4beta2 nicotinic acetylcholine receptor (nAChR) is a molecular target of MDMA. Since, the two MDMA enantiomers exhibit different pharmacological profiles, we have provided the molecular basis for the distinct psychostimulant profiles of the MDMA enantiomers mediated by the alpha4beta2 nAChR subtype.

Recommended citation: Llabrés S., García-Ratés S., Cristóbal-Lecina E., Riera A., Borrell JI., Camarasa J., Pubill D., Luque FJ., Escubedo E. (2014) European Journal of Medicinal Chemistry, 81, 35-46. https://www.sciencedirect.com/science/article/pii/S0223523414003651

Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus

Published in Journal of Medicinal Chemistry, 2014

Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. Here we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine able inhibit to the wild type as well as the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC50.

Recommended citation: Rey-Carrizo M., Barniol-Xicota M., Ma C., Frigolé-Vivas M., Torres E., Naessens L., Llabrés S., Juárez-Jiménez J., Luque FJ., DeGrado W., Lamb R., Pinto L., Vázquez S (2014). Journal of Medicinal Chemistry. 57, 5738-5747 https://pubs.acs.org/doi/abs/10.1021/jm5005804

New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode

Published in Eurupean Journal of Medicinal Chemistry, 2015

Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.02,10.03,7.09,11]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.02,5.03,11.04,9.06,17.012,16]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant.

Recommended citation: Rey-Carrizo M., Gazzarrini S., Frigolé-Vivas M., Llabrés S., Juárez-Jiménez J., Font-Bardia M., Naesens L., Moroni A., Luque FJ., Vázquez S. (2015) Eurupean Journal of Medicinal Chemistry. 96, 318-329. https://www.sciencedirect.com/science/article/pii/S0223523415002895

Mechanism of the Pseudoirreversible Binding of Amantadine to the M2 Proton Channel

Published in Journal of the American Chemical Society, 2016

The M2 proton channel of influenza A virus is an integral membrane protein involved in the acidification of the viral interior, a step necessary for the release of the viral genetic material and replication of new virions. Here we explore the mechanism of drug (un)binding to the M2 channel in order to gain insight into the structural and energetic features relevant for the development of novel inhibitors using multiple independent molecular dynamics simulations, exploratory conventional metadynamics, and multiple-walkers well-tempered metadynamics calculations.

Recommended citation: Llabrés S., Juárez-Jiménez J., Masetti M., Leiva R., Vázquez S., Gazzarrini S., Moroni A., Cavalli A., Luque FJ. (2016) Journal of the American Chemical Society, 2016, 138, 47, 15345–15358 https://pubs.acs.org/doi/abs/10.1021/jacs.6b07096

Structure of the MacAB–TolC ABC-type tripartite multidrug efflux pump

Published in Nature Microbiology, 2017

The MacA–MacB–TolC assembly of Escherichia coli is a transmembrane machine that spans the cell envelope and actively extrudes substrates, including macrolide antibiotics and polypeptide virulence factors. These transport processes are energized by the ATPase MacB, a member of the ATP-binding cassette (ABC) superfamily. We present the first electron cryo-microscopy structure of the ABC-type tripartite assembly at near-atomic resolution.

Recommended citation: Fitzpatrick AWP., Llabrés S., Neuberger A., Blaza JN., Bai X., Okada U., Murakami S., van Veen HW, Zachariae U., Scheres S.H.W., Luisi B.F. Du D. (2017) Nature Microbiology. 2, 17070. hhttps://www.nature.com/articles/nmicrobiol201770

Modulation of the Neisseria gonorrhoeae drug efflux conduit MtrE

Published in Scientific Reports, 2017

Widespread antibiotic resistance, especially of Gram-negative bacteria, has become a severe concern for human health, including Neisseria gonorrhoeae, one of the first bacteria for which pan-resistance. Here we present the electrophysiological characterisation of the outer membrane component MtrE and the membrane fusion protein MtrC from the most expressed efflux complex MtrCDE in Neisseria gonorrhoeae, obtained by a combination of planar lipid bilayer recordings and in silico techniques.

Recommended citation: Tamburrino G., Llabrés S., Vickery ON., Pitt SJ., Zachariae U. (2017) Scientific Reports, 7, 17091 https://www.nature.com/articles/s41598-017-16995-x

The O-GlcNAc Transferase Intellectual Disability Mutation L254F Distorts the TPR Helix

Published in Cell Chemical Biology, 2018

O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) transferase (OGT) regulates protein O-GlcNAcylation, an essential post-translational modification. Using a multi-disciplinary approach we show that the L254F OGT mutation, which is associated with intellectual disability, leads to conformational changes of the tetratricopeptide repeats and reduced activity, revealing the molecular mechanisms contributing to pathogenesis.

Recommended citation: Gundogdu M., Llabrés S., Gorelik A., Ferenbach AT., Zachariae U, van Aalten DMF. (2018) Cell Chemical Biology, 25, 5, 513. https://www.sciencedirect.com/science/article/pii/S2451945618300837

High-resolution experimental and computational electrophysiology reveals weak β-lactam binding events in the porin PorB

Published in Scientific Reports, 2019

The permeation of most antibiotics through the outer membrane of Gram-negative bacteria occurs through porin channels. Here we show that a combination of high-resolution electrophysiology, new noise-filtering analysis protocols and atomistic biomolecular simulations reveals weak binding events between the β-lactam antibiotic ampicillin and the porin PorB from the pathogenic bacterium Neisseria meningitidis.

Recommended citation: Bartsch A., Llabrés S., Pein F., Kattner C., Schön M., Diehn M., Tanabe M., Munk A., Zachariae U., Steinem C. (2019) Scientific Reports, 9, 1264. https://www.nature.com/articles/s41598-018-37066-9

Disease related single point mutations alter the global dynamics of a tetratricopeptide (TPR) α-solenoid domain

Published in Journal of Structural Biology, 2020

The enzyme O-linked GlcNAc-transferase (OGT), which catalyses O–GlcNAcylation of a broad range of substrate proteins, contains a tetratricopeptide repeat (TPR) domain that form a superhelical motiff. A number of single-point mutations in the TPR domain of human OGT have been associated with the disease Intellectual Disability (ID). We show that the OGT-TPR domain acts as an elastic nanospring, and that each of the ID-related local mutations substantially affect the global dynamics of the TPR domain, and therefore the OGT ability to bind and release OGT substrates.

Recommended citation: Llabrés S, Tsenkov MI, MacGowan SA, Barton GJ, Zachariae U (2020) Journal of Structural Biology. 209, 107405. https://www.sciencedirect.com/science/article/pii/S1047847719302266

On the Binding of Congo Red to Amyloid Fibrils

Published in Angewandte Chemie International Edition, 2020

Amyloids are characterized by their capacity to bind Congo red (CR), one of the most used amyloid‐specific dyes. Here, we combine spectroscopic data with molecular docking, molecular dynamics, and excitonic quantum/molecular mechanics calculations to examine and rationalize Congo red (CR) binding to amyloids. Our results explain the bathochromic shift in the maximal absorbance wavelength when CR is bound to amyloids.

Recommended citation: Espargaró A, Llabrés S, Saupe SJ, Curutchet C, Luque FJ, Sabaté R (2020) Angewandte Chemie International Edition. 132, 8181–8184. https://onlinelibrary.wiley.com/doi/abs/10.1002/ange.201916630

Combining Virtual Reality Visualization with Ensemble Molecular Dynamics to Study Complex Protein Conformational Changes

Published in Journal of Chemical Information and Modelling, 2020

We describe a framework that combines ensemble MD simulations and virtual reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins.

Recommended citation: Juárez-Jiménez J, Tew P, O′Connor M, Llabrés S, Sage R, Glowacki D and Michel J (2020) Journal of Chemical Information and Modelling, 60, 6344-6354. https://pubs.acs.org/doi/abs/10.1021/acs.jcim.0c00221

An antibiotic-resistance conferring mutation in a neisserial porin: Structure, ion flux, and ampicillin binding

Published in Biochimica et Biophysica Acta (BBA)-Biomembranes, 2021

We show that a single point mutation in the porin PorB from Neisseria meningitidis can strongly affect the binding and permeation of beta-lactam antibiotics

Recommended citation: Bartsch A, Ives CM, Kattner C, Pein F, Diehn M, Tanabe M, Munk A, Zachariae U, Steinem C, Llabrés S (2021) Biochimica et Biophysica Acta - Biomembranes. 1863:183601. https://www.sciencedirect.com/science/article/pii/S0005273621000523

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