Raúl Mera‐Adasme

University of Tarapacá

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Moisés Domínguez

Universidad de Santiago de Chile

Dage Sundholm

University of Helsinki

Paulo C. T. Souza

Inserm

‪J

‪Siewert J. Marrink

University of Groningen

Rocío Araya‐Osorio

University of Tarapacá

Luís Borges-Araújo

École Normale Supérieure de Lyon

Sangwook Wu

Pukyong National University

Fernando Mendizábal

University of Chile

Riccardo Alessandri

University of Chicago

Christian Ochsenfeld

Ludwig-Maximilians-Universität München

Cooperative Institutions

Universidad de Santiago de Chile

University of Helsinki

University of Chile

Centre National de la Recherche Scientifique

Universidad Bernardo O'Higgins

Université Claude Bernard Lyon 1

University of Groningen

Universidad Andrés Bello

Ludwig-Maximilians-Universität München

Universidad de Oviedo

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An Allosteric Pathway in Copper, Zinc Superoxide Dismutase Unravels the Molecular Mechanism of the G93A Amyotrophic Lateral Sclerosis-Linked Mutation

The Journal of Physical Chemistry Letters (2019)

Paulo C. T. Souza Sebastian Thallmair ‪Siewert J. Marrink Raúl Mera‐Adasme

Several different mutations of the protein copper, zinc superoxide dismutase (SOD1) produce the neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The molecular mechanism by which the diverse mutations converge to a similar pathology is currently unknown. The electrostatic loop (EL) of SOD1 is known to be affected in all of the studied ALS-linked mutations of SOD1. In this work, we employ a multiscale simulation approach to show that this perturbation corresponds to an increased probability of the EL detaching from its native position, exposing the metal site of the protein to water. From extensive atomistic and coarse-grained molecular dynamics (MD) simulations, we identify an allosteric pathway that explains the action of the distant G93A mutation on the EL. Finally, we employ quantum mechanics/molecular mechanics MD simulations to show that the opening of the EL decreases the Zn(II) affinity of the protein. As the loss of Zn(II) is at the center of several proposed pathogenic mechanisms in SOD1-linked ALS, the structural effect identified here not only is in agreement with the experimental data but also places the opening of the electrostatic loop as the possible main pathogenic effect for a significant number of ALS-linked SOD1 mutations.

Molecular mechanics

Dismutase

10.1021/acs.jpclett.9b02868

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Bartender: Martini 3 Bonded Terms via Quantum Mechanics-based Molecular Dynamics

Gilberto P. Pereira Riccardo Alessandri Moisés Domínguez Rocío Araya‐Osorio Linus Grünewald

Coarse-grained (CG) molecular dynamics (MD) simulations have grown in applicability over the years. The recently released version of the Martini CG force field (Martini 3) has been successfully applied to simulate many processes, including protein-ligand binding. However, the current ligand parameterization scheme is manual and requires an a priori reference all-atom (AA) simulation for benchmarking. For systems with suboptimal AA parameters, which are often unknown, this translates into a CG model which does not reproduce the true dynamical behavior of the underlying molecule. Here we present Bartender, a quantum mechanics (QM)/MD-based parameterization tool written in Go. Bartender harnesses the power of QM simulations and produces reasonable bonded terms for Martini 3 CG models of small molecules in an efficient and user-friendly manner. For small, ring-like molecules, Bartender generates models whose properties are indistinguishable from the human-made models. For more complex, drug-like ligands, it is able to fit functional forms beyond simple harmonic dihedrals, and thus better captures their dynamical behavior. Bartender has the power to both increase the efficiency and the accuracy of Martini 3-based high-throughput applications by producing stable and physically realistic CG models.

Force Field

10.26434/chemrxiv-2024-62kh1-v2

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Rotational rate coefficients of SN+(1Σ) by collision with He

Monthly Notices of the Royal Astronomical Society (2018)

Lisán David Cabrera‐González Raúl Mera‐Adasme Dayán Páez‐Hernández Otoniel Denis‐Alpizar

The SN+ ion has been detected for the first time in the interstellar medium (ISM) very recently. The analysis of the physical–chemical conditions of the regions where this molecule has been observed requires accurate collisional rates coefficients with the most common colliders in the ISM. The main goals of this work are to study the collision of SN+ with He and report the collisional rate coefficients for this system. A three-dimensional potential energy surface was developed from ab initio energies at the CCSD(T)/aug-cc-pV5Z level of theory fitted using a procedure based on the reproducing kernel Hilbert space approach. Close coupling calculations were performed, and the rate coefficients for the lowest 27 rotational states of SN+ are reported. Furthermore, the rate coefficients considering the hyperfine transitions are also explored.

10.1093/mnras/sty2252

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Martini 3 building blocks for Lipid Nanoparticle design

Lisbeth R. Kjølbye Mariana Valério Markéta Paloncýová Luís Borges-Araújo Roberto Pestana-Nobles

Lipid nanoparticles (LNPs) represent a promising platform for advanced drug and gene delivery, yet optimizing these particles for specific cargos and cell targets poses a complex, multifaceted challenge. Furthermore, there is a pressing need for a more comprehensive understanding of the underlying technology. Experimental studies are costly and often provide low-resolution information. Molecular dynamics (MD) simulations allow us to study these particles at a higher resolution, enhancing our understanding. However, studying these systems at atomic resolutions is both challenging and computationally expensive, as well as time-consuming. Coarse-grained (CG) models, such as Martini 3, are positioned as promising tools for studying LNPs. To enable CG-MD studies of LNPs, accurate and validated models of their components are needed. Here, we present a substantial extension of the Martini 3 library of lipids, covering the most important LNP components, including over a hundred of ionizable lipid (IL) models, along with natural occurring sterol models and PEGylated lipid models. We furthermore present initial protocols for screening fusion efficacy across different lipid formulations and for constructing whole LNPs at CG resolution, enabling future studies of these nanoparticles.

10.26434/chemrxiv-2024-bf4n8

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Martini 3 building blocks for Lipid Nanoparticle design

Lisbeth R. Kjølbye Mariana Valério Markéta Paloncýová Luís Borges-Araújo Roberto Pestana-Nobles

10.26434/chemrxiv-2024-bf4n8-v2

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Destabilization of the metal site as a hub for the pathogenic mechanism of five ALS-linked mutants of copper, zinc superoxide dismutase

Metallomics (2016)

Raúl Mera‐Adasme Hannes Erdmann Tomasz Bereźniak Christian Ochsenfeld

Residues with carbons in magenta are affected by five ALS-causing mutations. This work elucidates a common pathogenic mechanism for these mutations, linked to destabilization of the metal site.

10.1039/c6mt00085a

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A Practical Introduction to Martini 3 and its Application to Protein-Ligand Binding Simulations

Riccardo Alessandri Sebastian Thallmair Cristina Gil Herrero Raúl Mera‐Adasme ‪Siewert J. Marrink

Martini 3 is the new version of a widely used coarse-grained (CG) model that have been extensively parameterized to reproduce experimental and thermodynamic data. Based on a building-block approach, the new version shows a better coverage of the chemical space and more accurate predictions of interactions and molecular packing in general. Given these improvements, the Martini 3 model allows new applications such as studies involving protein–ligand interactions. In this chapter, a summary of the key elements of the new Martini version is presented, followed by an example of a practical application: a simulation of caffeine binding to the buried pocket of the adenosine A2A receptor, which is part of the GPCR family. Formulated as a hands-on tutorial, this chapter contains guidelines to build CG models of important systems, such as small drug-like molecules, transmembrane proteins, and lipid membranes. Finally, the last sections contain an outlook of possible future developments and notes describing useful information, limitations, and tips about Martini.

10.1063/9780735425279_001

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Glyphosate Mimics 17β-Estradiol Effects Promoting Estrogen Receptor Alpha Activity in Breast Cancer Cells

SSRN Electronic Journal (2022)

Juan P. Muñoz Rocío Araya‐Osorio Raúl Mera‐Adasme Gloria M. Calaf

Glyphosate, the active ingredient in several broad-spectrum herbicide formulations, has been validated and widely used throughout the world. Recent reports have questioned its safety, showing that glyphosate may act as an endocrine disruptor by promoting estrogenic activity. However, the molecular mechanism involved in this phenomenon remains unclear. Therefore, here we aimed to elucidate the mechanism by which glyphosate induces estrogenic activity using estrogen-sensitive breast cancer cell line models. Our results show that glyphosate mimics the cell effects of 17β-estradiol (E2), promoting estrogen receptor α (ERα) phosphorylation, its degradation, and transcriptional activity at high concentrations. The molecular mechanism seems involved in the ERα ligand-binding domain (LBD). Molecular simulations suggest a plausible interaction between glyphosate and the LBD through a coordinated complex involving divalent cations such as Zn (II). In addition, glyphosate exposure alters the level of Cyclin-dependent kinase 7 that contribute to ERα phosphorylation. Finally, glyphosate at high concentrations increases the cell proliferation rate and levels of cell cycle regulators, accompanied by an increase in anchorage-independent growth capacity. These findings suggest that glyphosate at high concentrations, induces estrogen-like effects through an ERα ligand binding site-dependent mechanism, leading to cellular responses resulting from a complex interplay of genomic and non-genomic events.

Estrogen receptor alpha

Alpha (finance)

Estrogen receptor beta

Estrogen-related receptor alpha

Estrogen-related receptor gamma

10.2139/ssrn.4202039

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Glutamyl-glutamate – a tailor-made chelating ligand for the [Be₄O]⁶⁺ core in basic beryllium complexes and implications on investigations on the origins of chronic beryllium disease

Zeitschrift für Naturforschung B (2015)

Raphael J. F. Berger Raúl Mera‐Adasme

Abstract Density functional theory calculations suggest that l -glutamyl- l -glutamate [H-Glu-Glu-H] 2– can act as an efficient chelating ligand in basic beryllium carboxylates of type Be 4 O(RCO 2 ) 6 . An exergonic energy balance of –10.6 kcal mol –1 for the substitution of two [AcO] – anions by one [H-Glu-Glu-OH] 2– dianion in Be 4 O(AcO 2 ) 6 has been calculated; for a second and third substitutions, the computed energy release amounts to –9.3, and –11.3 kcal mol –1 . The coordination geometry of the complexes shows a trend toward less deviation from local octahedral symmetry with increasing number of [H-Glu-Glu-OH] 2– ligands. The implications of these findings for the yet unknown molecular origins of chronic beryllium disease (CBD) are discussed, and a Be 4 O moiety is suggested as the beryllium species engaged in CBD.

Moiety

Exergonic reaction

10.1515/znb-2015-0157

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Citations (14)

Insights into the halochromism of a bithiophene π* probe

Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy (2019)

Moisés Domínguez Raúl Mera‐Adasme Marcos Caroli Rezende

10.1016/j.saa.2019.117264

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Citations (3)