Interaction of POPC, DPPC, and POPE with the μ Opioid Receptor:A Coarse-Grained Molecular Dynamics Study

<div><p>The μ opioid receptor (μOR), which is part of the G protein-coupled receptors family, is a membrane protein that is modulated by its lipid environment. In the present work, we model μOR in three different membrane systems: POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine), and DPPC (1, 2-dipalmitoyl-sn-glycero-3-phosphocholine) through 45 μs molecular dynamics (MD) simulations at the coarse-grained level. Our theoretical studies provide new insights to the lipid-induced modulation of the receptor. Particularly, to characterize how μOR interacts with each lipid, we analyze the tilt of the protein, the number of contacts occurring between the lipids and each amino acid of the receptor, and the μOR-lipid interface described as a network graph. We also analyze the variations in the number and the nature of the protein contacts that are induced by the lipid structure. We show that POPC interacts preferentially with helix 1 (H1) and helices H5-H6, POPE, with H5-H6 and H6-H7, and DPPC, with H4 and H6. We demonstrate how each of the three lipids shape the structure of the μOR.</p></div

Self-assembly and chiroptical properties in supramolecular complexes of adenosine phosphates and guanidinium-bispyrene

International audienc

Detection of the Enzymatic Cleavage of DNA through Supramolecular Chiral Induction to a Cationic Polythiophene

International audienc

Hierarchical Self-Assembly and Multidynamic Responsiveness of Fluorescent Dynamic Covalent Networks Forming Organogels

International audienceSmart stimuli-responsive fluorescent materials are of interest in the context of sensing and imaging applications. In this project, we elaborated multidynamic fluorescent materials made of a tetraphenylethene fluorophore displaying aggregation-induced emission and short cysteine-rich C-hydrazide peptides. Specifically, we show that a hierarchical dynamic covalent self-assembly process, combining disulfide and acyl-hydrazone bond formation operating simultaneously in a one-pot reaction, yields cage compounds at low concentration (2 mM), while soluble fluorescent dynamic covalent networks and even chemically cross-linked fluorescent organogels are formed at higher concentrations. The number of cysteine residues in the peptide sequence impacts directly the mechanical properties of the resulting organogels, Young’s moduli varying 2500-fold across the series. These materials underpinned by a nanofibrillar network display multidynamic responsiveness following concentration changes, chemical triggers, as well as light irradiation, all of which enable their controlled degradation with concomitant changes in spectroscopic outputs─self-assembly enhances fluorescence emission by ca. 100-fold and disassembly quenches fluorescence emission

Revealing the Organization of Catalytic Sequence-Defined Oligomers via Combined Molecular Dynamics Simulations and Network Analysis

Similar to biological macromolecules such as DNA and proteins , the precise control over the monomer positi on in sequence-defined polymers is of paramount importance for tuning their structures and propertiest,o ward achieving specific functions. Here we apply molecular network analysis on 3D structures issued from molecular dynamics simulations to decipher how the chain organization of trifunctional catalytic oligomers is influenced by the oligomer sequence and the length of oligo(ethylene oxide) spacers. Our findings demonstrate that the tuning of their primary structure is crucial for favoring cooperative int eractions between the catalytic units and thus higher catalytic activities. This combined approach can assist in establishing structure-property relationships leading to a more rational design of sequence-defined catalytic oligomers via computational chemistry

Using nickel to fold discrete synthetic macromolecules into single-chain nanoparticles

Macromolecules found in Nature display a precise control over the primary as well as higher ordered architectures. To mimic the folding found in Nature, we herein demonstrate the design and characterization of single-chain nanoparticles that are formed by the folding of sequence-defined macromolecules with metal ions. The study showcases the influence of the loop size of such precision macromolecules on their relative hydrodynamic radius. The sequence-defined structures are fabricated using thiolactone chemistry, where two picolyl moieties are installed forming a valuable ligand system for subsequent metal complexation. Next, metal ions such as Ni(ii) and Cu(ii) ions are introduced to fold the unimers into sequence-defined single-chain nanoparticles (SD-SCNPs). After proving the successful complexation using a trimer, a systematic study is conducted altering the distance between the respective ligands by incorporating variable numbers of non-functionalized spacer units. Finally, the loop size formation of the SD-SCNPs is evidenced by DOSY measurements. The result indicates that the positioning of the ligands plays a crucial role on the compaction process and, more specifically, on the final size of the SD-SCNP. In addition, molecular dynamics (MD) simulations show the effects of the sequence and Ni(ii) complexation on the structure and compaction of the SD-SCNPs, and highlight the differences of the nanoparticles' shape when varying the number of spacer units. Finally, the system is further expanded to a dodecamer and even a heptadecamer with drastically decreased hydrodynamic radii after compaction

Superimposition of the binding site conformations observed at the 270^th (green) and 375^th (blue) ns frames, <i>i.e.</i>, the frames of the minimum and maximum POCASA volume, respectively, as deserved during the 0.5 <i>µ</i>s all-atom MD simulation of the <i>µ</i>OR structure.

<p>The three residues labelled, <i>i.e</i>., F153, W293, and Y326, are the only ones located in the minimum volume pocket. The corresponding residues of the binding site conformation related to the maximum POCASA volume are presented in red.</p

On the Modularity of the Intrinsic Flexibility of the <i>µ</i> Opioid Receptor: A Computational Study

<div><p>The <i>µ</i> opioid receptor (<i>µ</i>OR), the principal target to control pain, belongs to the G protein-coupled receptors (GPCRs) family, one of the most highlighted protein families due to their importance as therapeutic targets. The conformational flexibility of GPCRs is one of their essential characteristics as they take part in ligand recognition and subsequent activation or inactivation mechanisms. It is assessed that the intrinsic mechanical properties of the <i>µ</i>OR, more specifically its particular flexibility behavior, would facilitate the accomplishment of specific biological functions, at least in their first steps, even in the absence of a ligand or any chemical species usually present in its biological environment. The study of the mechanical properties of the <i>µ</i>OR would thus bring some indications regarding the highly efficient ability of the <i>µ</i>OR to transduce cellular message. We therefore investigate the intrinsic flexibility of the <i>µ</i>OR in its apo-form using all-atom Molecular Dynamics simulations at the sub-microsecond time scale. We particularly consider the <i>µ</i>OR embedded in a simplified membrane model without specific ions, particular lipids, such as cholesterol moieties, or any other chemical species that could affect the flexibility of the <i>µ</i>OR. Our analyses highlighted an important local effect due to the various bendability of the helices resulting in a diversity of shape and volume sizes adopted by the <i>µ</i>OR binding site. Such property explains why the <i>µ</i>OR can interact with ligands presenting highly diverse structural geometry. By investigating the topology of the <i>µ</i>OR binding site, a conformational global effect is depicted: the correlation between the motional modes of the extra- and intracellular parts of <i>µ</i>OR on one hand, along with a clear rigidity of the central <i>µ</i>OR domain on the other hand. Our results show how the modularity of the <i>µ</i>OR flexibility is related to its pre-ability to activate and to present a basal activity.</p></div