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Glycine receptors (GlyR) are regulated by small-molecule binding at several allosteric sites. Endocannabinoids like tetrahydrocannabinol (THC) and N-arachidonyl-ethanolamide (AEA) potentiate GlyR but their binding site is unknown. Using millisecond coarse-grained MD simulations powered byMartini 3we have characterized their binding site(s) at the Zebrafish GlyR-α1 with atomic resolution. Based on hundreds of thousand ligand-binding events, we find that cannabinoids bind at both intrasubunit and intersubunit sites in the transmembrane domain. For THC, intrasubunit binding is in excellent agreement with recent cryo-EM structures, while intersubunit binding recapitulates in full previous mutagenesis experiments. Surprisingly, AEA is found to bind at the same intersubunit site despite the strikingly different chemistry. Statistical analyses of the ligand-receptor interactions highlight potentially relevant residues for GlyR potentiation offering experimentally testable predictions. The results highlight an unanticipated complexity underlying allosteric regulation at synaptic receptors and establish an original simulation protocol for the identification and characterization of allosteric binding sites.

Calixarenes are hallmark molecules in supramolecular chemistry as guest cages for small ligands. They have also conversely proved their interest as auxiliary ligands toward assisted co-crystallization of proteins. These functionalized macromolecular cages target positively-charges residues, and notably surface-exposed lysines, with a site-selectivity finely characterized experimentally, but that remains to be assessed. Relying on a tailored molecular dynamics simulations protocol, we explore the association of para-sulfonato-calix[4]arenes with an antifungal protein, as a small yet most competitive system with 13 surface-exposed lysines. Our computational approach probe "de novo" the electrostatically-driven interaction, ruled out by a competition with salt bridges, not only corroborating the main binding site probed by X-ray, but also characterizing a second binding site that can act as a transient hub spot. The attach-pull-release (APR) method provides a very good assessment of the overall binding free energy measured experimentally (-6.42+-0.5 vs -5.45 kcal.mol-1 by isothermal titration calorimetry). This work also probes dynamical allosteric modifications upon ligand binding, and our computational protocol could be generalized to situate the supramolecular forces ruling out the calixarene-assisted co-crystallization of proteins.

International audience; Lanthanide complexes are now widely used as powerful auxiliaries for protein crystallisation to improve the crucial nucleation and phasing steps. We systematically analysed the influence of the commercial crystallisation kit composition on the efficiency of two lanthanide additives [Na]$_3$[Eu(DPA)$_3$] and Tb-Xo4, we developed. This study revealed that our initial the trisdipicolinate complex presents a lower chemical stability and a strong tendency to self-crystallisation detrimental for its use in highthroughput robotised crystallisation platform. In particular, we reported herein the crystal structures of (Mg(H$_2$O)$_6$)$_3$ [Eu(DPA)$_3$]$_2$•7H$_2$O (1),{(Ca(H$_2$O)$_4$)$_3$[Eu(DPA)$_3$]$_2$}$_n$•11nH$_2$O (2) and {Cu(DPA)(H$_2$O)$_2$}$_n$ (3) resulting from spontaneous crystallisation in the presence of divalent alkaline earth cation or transmetallation. On the other hand, the Tb-Xo4 is perfectly soluble in the crystallisation media, stable in the presence of alkaline-earth dications and slowly decomposed (within days) by trans-metalation with transition metals. The original structure of [Tb$_4$L$_4$(H$_2$O)$_4$]Cl$_4$•15H$_2$O (4) is also described. In this article, we also discussed the potential beneficial interactions between the crystallisation mixture components and Tb-Xo4 leading to the formation of more complex adducts observed in the case of the AdKA protein crystallisation, like {AdkA/Tb-Xo4/Mg$^{2+}$ /glycerol} in the protein binding sites. The observation of such multi-components adducts illustrates the complexity and the versatility of the supramolecular chemistry occurring at the surface of proteins.

Sequence dependence of the (6–4) photoproduct conformational landscape when embedded in six 25-bp duplexes is evaluated along extensive unbiased and enhanced (replica exchange with solute tempering, REST2) molecular dynamics simulations. The structural reorganization as the central pyrimidines become covalently tethered is traced back in terms of non-covalent interactions, DNA bending, and extrusion of adenines of the opposite strands. The close sequence pattern impacts the conformational landscape around the lesion, inducing different upstream and downstream flexibilities. Moreover, REST2 simulations allow us to probe structures possibly important for damaged DNA recognition.

Sequence dependence of the (6-4)photoproduct dynamics when embedded in six 25-bp duplexes is evaluated along extensive unbiased and enhanced (replica exchange with solute tempering, REST2) molecular dynamics simulations. The structural reorganization as the central pyrimidines become covalently tethered is traced back in terms of non-covalent interactions, DNA bending and extrusion of adenines of the opposite strands. The close sequence pattern impacts the conformational landscape around the lesion, inducing a different upstream and downstream flexibilities. Moreover, REST2 simulations allow to probe structures possibly important for damaged DNA recognition.

In the realm of biomolecules, peptides can present a large diversity of structures. Our study sheds new light on the structural interplay between a tris-dipicolinate lanthanide probe and a decapeptide SASYKTLPRG. Although a rather trivial, electrostatically driven interaction was expected, the combination of paramagnetic NMR and molecular dynamics simulations reveals a highly dynamic association process and allows for providing extensive insights into the interaction sites and their occupancy. This study highlights the importance of a large conformational sampling to reconcile characteristic time in NMR with molecular dynamics simulations, where sampling in the microsecond range is needed. This study opens the door for a detailed mechanistic elucidation of the early steps of lanthanide complex-peptide or lanthanide complex–protein interaction or self-assembly processes.

Here, we propose a molecular dynamics investigation of the supramolecular association of sulfonatedcalix-[8]-arenes to cytochrome c. The binding sites prone to interactions with sulfonated calixarenescan be identified without prior knowledge of the X-ray structure, and the binding free energiesestimated by molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) post-analysis arefound to be in neat agreement with the isothermal titration calorimetry (ITC) measurements The per-residuedecomposition reveals the detailed picture of this electrostatically-driven association and notably therole of the arginine R13 as a bridge residue between the two main anchoring sites. In addition,the analysis of the residue behavior by means of a supervised machine learning protocol unveils the formation of an hydrogen bond network far from the binding sites, increasing the rigidity of theprotein.

The autoionization dynamics of water molecules induced by Ne∗(3P2,0) collisions has been studied. The energy dependence of the total ionization cross section is measured together with relative abundances of product ions in the 0.05–0.15 eV range. The data are analyzed by using an optical potential model within a semiclassical approach. The real part of the potential is formulated applying a semiempirical method, while the imaginary part has been used in the fitting procedure of the data adjusting its pre-exponential factor. The good agreement between calculations and experiment confirms the attractive nature of the potential energy surface driving the Ne∗–H2O dynamics.

New molecular beam scattering experiments have been performed to measure the total (elastic plus inelastic) cross sections as a function of the velocity in collisions between water and hydrogen sulfide projectile molecules and the methane target. Measured data have been exploited to characterize the range and strength of the intermolecular interaction in such systems, which are of relevance as they drive the gas phase molecular dynamics and the clathrate formation. Complementary information has been obtained by rotational spectra, recorded for the hydrogen sulfide–methane complex, with a pulsed nozzle Fourier transform microwave spectrometer. Extensive ab initio calculations have been performed to rationalize all the experimental findings. The combination of experimental and theoretical information has established the ground for the understanding of the nature of the interaction and allows for its basic components to be modelled, including charge transfer, in these weakly bound systems. The intermolecular potential for H2S–CH4 is significantly less anisotropic than for H2O–CH4, although both of them have potential minima that can be characterized as ‘hydrogen bonded’.

Recent experiments on the title subject, performed with a high-resolution crossed-beam apparatus, have provided the total ionization cross sections as a function of the collision energy between noble gas atoms, electronically excited in their metastable states (Ng*), and H2 O, H2 S, and NH3 reagents, as well as the emitted electron energy spectra. This paper presents a rationalization of all the experimental findings in a unifying picture to cast light on the basic chemical properties of Ng* under conditions of great relevance both from a fundamental and from an applied point of view. The importance of this investigation is that it isolates the selective role of the intermolecular halogen and hydrogen bonds, to assess their anisotropic effects on the stereodynamics of the promoted ionization reactions, and to model energy transfer and reactivity in systems of applied interest, such as planetary atmospheres, plasmas, lasers, and flames.

The systems studied in this work are gas-phase weakly bound adducts of the noble-gas (Ng) atoms with CCl4 and CF4. Their investigation was motivated by the widespread current interest for the intermolecular halogen bonding (XB), a structural motif recognized to play a role in fields ranging from elementary processes to biochemistry. The simulation of the static and dynamic behaviors of complex systems featuring XB requires the formulation of reliable and accurate model potentials, whose development relies on the detailed characterization of strength and nature of the interactions occurring in simple exemplary halogenated systems. We thus selected the prototypical Ng-CCl4 and Ng-CF4 and performed high-resolution molecular beam scattering experiments to measure the absolute scale of their intermolecular potentials, with high sensitivity. In general, we expected to probe typical van der Waals interactions, consisting of a combination of size (exchange) repulsion with dispersion/induction attraction. For the He/Ne-CF4, the analysis of the glory quantum interference pattern, observable in the velocity dependence of the integral cross section, confirmed indeed this expectation. On the other hand, for the He/Ne/Ar-CCl4, the scattering data unravelled much deeper potential wells, particularly for certain configurations of the interacting partners. The experimental data can be properly reproduced only including a shifting of the repulsive wall at shorter distances, accompanied by an increased role of the dispersion attraction, and an additional short-range stabilization component. To put these findings on a firmer ground, we performed, for selected geometries of the interacting complexes, accurate theoretical calculations aimed to evaluate the intermolecular interaction and the effects of the complex formation on the electron charge density of the constituting moieties. It was thus ascertained that the adjustments of the potential suggested by the analysis of the experiments actually reflect two chemically meaningful contributions, namely, a stabilizing interaction arising from the anisotropy of the charge distribution around the Cl atom in CCl4 and a stereospecific electron transfer that occurs at the intermolecular distances mainly probed by the experiments. Our model calculations suggest that the largest effect is for the vertex geometry of CCl4 while other geometries appear to play a minor to negligible role. (C) 2015 AIP Publishing LLC.

The main point of this paper concerns the theoretical characterisation of the effects induced by the intermolecular interaction on the electron density upon the formation of CH4-H2X (X=O,S) and CH4-Ng (Ng=Ar,Xe) complexes. The work has been stimulated by recent molecular scattering beams experiments, which point out differences in both strength and anisotropy of the intermolecular potential between CH4-H2X respect to reference CH4-Ng systems. Herein, attention is focused on the electronic charge polarisation and particularly charge transfer (CT) effects between involved partners, directly related to the topology of the full potential energy surface. The modification of electron density and the occurrence of CT have been evaluated via the charge displacement function worked out by high level ab initio calculations. Moreover, in the case of a specific configuration of CH4-H2O system, we define the leading interaction components, including their relative stabilising role and test our intermolecular potential model with reference to ab initio calculations. The results obtained indicate that CT clearly affects the strength and the anisotropy of CH4-H2O complex, and covers a minor and negligible role for CH4-H2S and the noble gas complexes, respectively.

The complexes of helium and neon with gaseous neutral molecules are generally perceived to be van der Waals adducts held together by physical (non-covalent) forces, owing to the combination of size (exchange) repulsion with dispersion/induction attraction. Molecular beam experiments confirm that this is the case for He-CF4 , Ne-CF4 adducts, but revealed that the interaction of He and Ne with CCl4 features an appreciable contribution of chemical components that arise from the anisotropy of the electron density of CCl4 that enhances a charge transfer from Ng (Ng=He, Ne). These findings furnish a novel assay of the bonding capabilities of helium and neon, and invite to revisit the neutral complexes of these elements as systems of chemical relevance. The CCl4 -Ng are also peculiar examples of halogen bonds, a group of interactions of major current concern. Finally, this investigation is a prelude to the development of semi-empirical models for force fields aimed to the unified description of static and dynamical properties of systems of comparable or higher complexity.

New molecular beam scattering experiments are reported for the H2S-H-2 system recording, under high angular and velocity resolution conditions, the "glory" quantum interference in the velocity dependence of the total cross section. The analysis of the experimental data permits the determination, for the first time, of a spherically averaged intermolecular potential for this system. An evaluation of significant cuts of the potential energy surface, obtained by accurate ab initio CCSD(T) calculations using large basis sets, combined with the analysis of the electronic charge displacement accompanying the formation of H2S-H-3, has been also performed in order to rationalize the experimental findings. A direct comparison with the analogous water-hydrogen complex (Belpassi, L. et al. J. Am. Chem. Soc. 2010, 132, 13046), investigated with the same experimental conditions and theoretical methodology, brings to light detailed differences in the intermolecular interaction affecting the observables. In particular, it shows the important fact that the charge transfer (CT) component of the interaction plays a minor role in H2S-H-3, whereas it was found to be a crucial stabilization component of the interaction in water-H-2, determining the potential energy surface anisotropy and the precise location of the energy minima.

Potential energy surfaces for the interaction of a Ne * ( 3 P 2,0 ) atom with H 2 O and H 2 S molecules are obtained on the basis of a semi empirical method that has been previously used for some specific orientations in Ne * ( 3 P 2,0 )–H 2 O system. The method is now suitable for all orientations and also for Ne * ( 3 P 2,0 )–H 2 S system. Interesting features emerge by comparing the two systems and appear related to different characteristics of the two molecular partners. The potential energy surface for Ne * ( 3 P 2,0 )–H 2 S has been also successfully tested for reproducing recent experimental Penning ionization electron spectroscopy data, sensible to some specific orientations of the two colliding partners.

The autoionization dynamics of triatomic molecules induced by He*(23,1S1,0) and Ne*(3P2,0) collisions has been discussed. The systems are analyzed by using an optical potential model within a semiclassical approach. The real part of the potential is formulated applying a semiempirical method, while the imaginary part has been used in the fitting procedure of the data adjusting its pre-exponential factor. The good agreement between calculations and experiment confirms the attractive nature of the potential energy surface driving the He* and Ne*-H2O dynamics.

A combined analysis of both new (energy spectra of emitted electrons) and previously published (ionization cross sections) experimental data, measured under the same conditions and concerning electronically excited lighter noble gas -NH3 collisional autoionization processes, is carried out. Such an analysis, performed by exploiting a formulation of the full potential energy surface both in the real and imaginary parts, provides direct information on energetics, structure, and lifetime of the intermediate collision complex over all the configuration space. The marked anisotropy in the attraction of the real part, driving the approach of reagents, and the selective role of the imaginary component, associated to the charge transfer coupling between entrance and exit channels, suggests that reactive events occur almost exclusively in the molecular hemisphere containing the nitrogen lone pair. Crucial details on the stereo-dynamics of elementary collisional autoionization processes are then obtained, in which the open shell nature of the disclosed ionic core of metastable atom plays a crucial role. The same analysis also suggests that the strength of the attraction and the anisotropy of the interaction increases regularly along the series Ne*((3)P), He*((3)S), He*((1)S)-NH3. These findings can be ascribed to the strong rise of the metastable atom electronic polarizability (deformability) along the series. The obtained results can stimulate state of the art ab initio calculations focused on specific features of the transition state (energetics, structure, lifetime, etc.) which can be crucial for a further improvement of the adopted treatment and to better understand the nature of the leading interaction components which are the same responsible for the formation of the intermolecular halogen and hydrogen bond.