Description of non-covalent interactions in benzyl chalcocyanate crystals from smoothed Cromer-Mann electron density distribution functions.

A well-known method to characterize non-covalent interactions consists in the topological analysis of electron density distribution (EDD) functions, complemented by the search for minima in the reduced density gradient (RDG) distributions. Here, we characterize intermolecular interactions occurring in crystals of benzyl chalcocyanate compounds through bond critical points (BCP) of the promolecular electron density (ED) built from the crystallographic Cromer-Mann parameters, at several smoothing levelst. The trajectories formed by thet-dependent BCP locations are interpreted in terms of the intermolecular interactions occurring within the crystal arrangements. Chalcogen…nitro BCPs are clearly present in the unsmoothed EDDs but are annihilated astincreases, while chalcogen…chalcogen BCPs appear and are among the only BCPs left at the highest smoothing level. The chalcogen bonds are differentiated from the other chalcogen interactions through the linear chalcogen…BCP…nitro geometry at low smoothing level and their more negative Laplacian values. The annihilation of CPs can be followed by the apparition of a RDG minimum, associated with a very weak interaction. Along the BCP trajectories, the Laplacian shows a progressive concentration of the ED in the intermolecular space within the crystals and adopts the most negative values at the shortest atom…atom separations. At the termination point of a BCP trajectory, the drastic increase of the ellipticity value illustrates the flattening of the EDD.

Structure-based identification of inhibitors disrupting the CD2-CD58 interactions.

The immune system has very intricate mechanisms of fighting against the invading infections which are accomplished by a sequential event of molecular interactions in the body. One of the crucial phenomena in this process is the recognition of T-cells by the antigen-presenting cells (APCs), which is initiated by the rapid interaction between both cell surface receptors, i.e., CD2 located on T-cells and CD58 located on APCs. Under various pathological conditions, which involve undesired immune response, inhibiting the CD2-CD58 interactions becomes a therapeutically relevant opportunity. Herein we present an extensive work to identify novel inhibiting agents of the CD2-CD58 interactions. Classical molecular dynamics (MD) simulations of the CD2-CD58 complex highlighted a series of crucial CD58 residues responsible for the interactions with CD2. Based on such results, a pharmacophore map, complementary to the CD2-binding site of CD58, was created and employed for virtual screening of ~ 300,000 available compounds. On the ~ 6000 compounds filtered from pharmacophore mapping, ADME screening leads to ~ 350 molecules. Molecular docking was then performed on these molecules, and fifteen compounds emerged with significant binding energy (< - 50 kcal/mol) for CD58. Finally, short MD simulations were performed in triplicate on each complex (i) to provide a microscopic view of the ligand binding and (ii) to rule out possibly weak binders of CD58 from the identified hits. At last, we suggest eight compounds for in vitro testing that were identified as promising hits to bind CD58 with a high binding affinity.

Interaction of POPC, DPPC, and POPE with the µ opioid receptor: A coarse-grained molecular dynamics study.

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.

Investigating cyclic peptides inhibiting CD2-CD58 interactions through molecular dynamics and molecular docking methods.

The CD2-CD58 protein-protein interaction is known to favor the recognition of antigen presenting cells by T cells. The structural, energetics, and dynamical properties of three known cyclic CD58 ligands, named P6, P7, and RTD-c, are studied through molecular dynamics (MD) simulations and molecular docking calculations. The ligands are built so as to mimic the C and F ß-strands of protein CD2, connected via turn inducers. The MD analyses focus on the location of the ligands with respect to the experimental binding site and on the direct and water-mediated hydrogen bonds (H bonds) they form with CD58. Ligand P6, with a sequence close to the experimental ß-strands of CD2, presents characteristics that explain its higher experimental affinity, e.g., the lower mobility and flexibility at the CD58 surface, and the larger number and occurrence frequency of ligand-CD58 H bonds. For the two other ligands, the structural modifications lead to changes in the binding pattern with CD58 and its dynamics. In parallel, a large set of molecular docking calculations, carried out with various search spaces and docking algorithms, are compared to provide a consensus view of the preferred ligand binding modes. The analysis of the ligand side chain locations yields results that are consistent with the CD2-CD58 crystal structure and suggests various binding modes of the experimentally identified hot spot of the ligands, i.e., Tyr86. P6 is shown to form a number of contacts that are also present in the experimental CD2-CD58 structure.

Computational simulations determining disulfonic stilbene derivative bioavailability within human serum albumin.

Disulfonic stilbene (DS) derivatives are a member of the large family of compounds widely employed in medicine and biology as modulators for membrane transporters or inhibitors of a protein involved in DNA repair. They constitute interesting compounds that have not yet been investigated within the bioavailability framework. No crystallographic structures exist involving such compounds embedded in the most common drug carrier, human serum albumin (HSA). The present work studies, for the first time, the physico-chemical features driving the inclusion of three DS derivatives (amino, nitro and acetamido, named DADS, DNDS and DATDS, respectively) within the four common HSA binding sites using combined molecular docking and molecular dynamics simulations. A careful analysis of each ligand within each of the studied binding sites is carried out, highlighting specific interactions and key residues playing a role in stabilizing the ligand within each pocket. The comparison between DADS, DNDS and DATDS reveals that depending on the binding site, the conclusions are rather different. For instance, the IB binding site shows a specificity to DADS compounds while IIIA is the most favorable site for DNDS and DATDS.

Reduced Point Charge Models of Proteins: Effect of Protein-Water Interactions in Molecular Dynamics Simulations of Ubiquitin Systems.

We investigate the influence of various solvent models on the structural stability and protein-water interface of three ubiquitin complexes (PDB access codes: 1Q0W , 2MBB , 2G3Q ) modeled using the Amber99sb force field (FF) and two different point charge distributions. A previously developed reduced point charge model (RPCM), wherein each amino acid residue is described by a limited number of point charges, is tested and compared to its all-atom (AA) version. The complexes are solvated in TIP4P-Ew or TIP3P type water molecules, involving either the scaling of the Lennard-Jones protein-Owater interaction parameters, or the coarse-grain (CG) SIRAH water description. The best agreements between the RPCM and AA models were obtained for structural, protein-water, and ligand-ubiquitin properties when using the TIP4P-Ew water FF with a scaling factor γ of 0.7. At the RPCM level, a decrease in γ, or the inclusion of SIRAH particles, allows weakening of the protein-water interactions. It results in a slight collapse of the protein structure and a less compact hydration shell and, thus, in a decrease in the number of protein-water and water-water H-bonds. The dynamics of the surface protein atoms and of the water shell molecules are also slightly refrained, which allow the generation of stable RPCM trajectories.

The role of water in the elastic properties of aluminosilicate zeolites: DFT investigation.

The bulk and Young moduli and heats of hydration have been calculated at the DFT level for fully optimized models of all-siliceous and cationic zeolites with and without water, and then compared to the corresponding experimental data. Upon the addition of water, the monovalent alkali ion and divalent alkaline earth ion exchanged zeolites presented opposite trends in the elastic modulus. The main contribution to the decrease in the elastic modulus of the alkali ion exchanged zeolites appeared to be a shift of cations from the framework oxygen atoms upon water addition, with the coordination number often remaining the same. The contrasting increase in elastic modulus observed for the divalent (alkaline earth) ion exchanged zeolites was explained by cation stabilization resulting from increased coordination, which cannot be achieved within a rigid zeolite framework without water.

Parameterization of the ReaxFF reactive force field for a proline-catalyzed aldol reaction.

A parameterization of the ReaxFF reactive FF is performed using a Monte Carlo Simulated Annealing procedure for the modeling of a proline-catalyzed aldol reaction. Emphasis is put on the accurate reproduction of the relative stabilities of several key intermediates of the reaction, as well as, on the description of the reaction path bridging these intermediates based on quantum mechanical calculations. Our training sets include new criteria based on geometry optimizations and short Molecular Dynamics simulations to ensure that the trained ReaxFF potentials adequately predict the structures of all key intermediates. The transferability of the sets of parameters obtained is assessed for various steps of the considered aldol reaction, as well as for different substrates, catalysts, and reagents. This works indeed highlights the challenge of reaching transferable parameters for several reaction steps. © 2016 Wiley Periodicals, Inc.

Multiscale design of coarse-grained elastic network-based potentials for the µ opioid receptor.

Despite progress in computer modeling, most biological processes are still out of reach when using all-atom (AA) models. Coarse-grained (CG) models allow classical molecular dynamics (MD) simulations to be accelerated. Although simplification of spatial resolution at different levels is often investigated, simplification of the CG potential in itself has been less common. CG potentials are often similar to AA potentials. In this work, we consider the design and reliability of purely mechanical CG models of the µ opioid receptor (µOR), a G protein-coupled receptor (GPCR). In this sense, CG force fields (FF) consist of a set of holonomic constraints guided by an elastic network model (ENM). Even though ENMs are used widely to perform normal mode analysis (NMA), they are not often implemented as a single FF in the context of MD simulations. In this work, various ENM-like potentials were investigated by varying their force constant schemes and connectivity patterns. A method was established to systematically parameterize ENM-like potentials at different spatial resolutions by using AA data. To do so, new descriptors were introduced. The choice of conformation descriptors that also include flexibility information is important for a reliable parameterization of ENMs with different degrees of sensitivity. Hence, ENM-like potentials, with specific parameters, can be sufficient to accurately reproduce AA MD simulations of µOR at highly coarse-grained resolutions. Therefore, the essence of the flexibility properties of µOR can be captured with simple models at different CG spatial resolutions, opening the way to mechanical approaches to understanding GPCR functions. Graphical Abstract All atom structure, residue interaction network and coarse-grained elastic network models of the µ opioid receptor (µOR).

A coarse-grained simulation study of the structures, energetics, and dynamics of linear and circular DNA with its ions.

We have studied the structural, energetics, and dynamical properties of a variety of linear and circular DNA fragments using a solvent-mediated coarse-grained (CG) model of DNA with explicit ions recently developed by us [Naômé et al., J. Chem. Theory Comput., 2014, 10, 3541-3549]. We particularly examined the treatment of electrostatics and determined that a large cutoff is necessary to properly reproduce the DNA flexibility. Moreover, it is crucial to include long-ranged electrostatic interactions: a Particle Mesh Ewald scheme at low resolution is sufficient to avoid structural artifacts. We calculated the ring closure probabilities, as j-factors, for DNA fragments of different lengths from equilibrium, as well as restrained molecular dynamics (MD) simulations. The latter force integration method provided accurate results without model fitting. We generated topology and energy maps for DNA minicircles of various lengths and helical densities, at low and high ion concentrations. A general trend for structure compaction is observed, driven by an increase in writhing as the ionic concentration increases. Finally, we applied a reconstruction procedure to generate detailed molecular structures from the various superhelical conformations generated by the CG MD of the DNA minicircles. These pre-equilibrated reconstructed atomistic structures can serve as starting material for atomistic simulations.

Systematic hierarchical coarse-graining with the inverse Monte Carlo method.

We outline our coarse-graining strategy for linking micro- and mesoscales of soft matter and biological systems. The method is based on effective pairwise interaction potentials obtained in detailed ab initio or classical atomistic Molecular Dynamics (MD) simulations, which can be used in simulations at less accurate level after scaling up the size. The effective potentials are obtained by applying the inverse Monte Carlo (IMC) method [A. P. Lyubartsev and A. Laaksonen, Phys. Rev. E 52(4), 3730-3737 (1995)] on a chosen subset of degrees of freedom described in terms of radial distribution functions. An in-house software package MagiC is developed to obtain the effective potentials for arbitrary molecular systems. In this work we compute effective potentials to model DNA-protein interactions (bacterial LiaR regulator bound to a 26 base pairs DNA fragment) at physiological salt concentration at a coarse-grained (CG) level. Normally the IMC CG pair-potentials are used directly as look-up tables but here we have fitted them to five Gaussians and a repulsive wall. Results show stable association between DNA and the model protein as well as similar position fluctuation profile.

Modeling of structural, energetic, and dynamic properties of few-atom silver clusters embedded in polynucleotide strands by using molecular dynamics.

This work concerns the study of the structural, energetic, and dynamic properties of fluorescent systems composed of silver clusters stabilized by polynucleotide strands. To do so, classical interaction potentials relative to silver, neutral and cationic, were introduced in the AMBER force field. Molecular dynamics simulations allowed analysis of the nature and force of the interactions between the various parts of the nucleic oligomers and the silver clusters. Conformational analyses were necessary to explore the flexibility of the supramolecular assemblies, specifically by radial distribution functions and Ramachandran-type maps.

On the modularity of the intrinsic flexibility of the µ opioid receptor: a computational study.

The µ opioid receptor (µOR), 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 µOR, 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 µOR would thus bring some indications regarding the highly efficient ability of the µOR to transduce cellular message. We therefore investigate the intrinsic flexibility of the µOR in its apo-form using all-atom Molecular Dynamics simulations at the sub-microsecond time scale. We particularly consider the µOR 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 µOR. 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 µOR binding site. Such property explains why the µOR can interact with ligands presenting highly diverse structural geometry. By investigating the topology of the µOR binding site, a conformational global effect is depicted: the correlation between the motional modes of the extra- and intracellular parts of µOR on one hand, along with a clear rigidity of the central µOR domain on the other hand. Our results show how the modularity of the µOR flexibility is related to its pre-ability to activate and to present a basal activity.

Investigation of ESIPT in a panel of chromophores presenting N-H∙∙∙N intramolecular hydrogen bonds.

Thermodynamic and kinetic aspects of excited state intramolecular proton transfer (ESIPT) are investigated in 11 chromophores harboring an intramolecular N-H∙∙∙N hydrogen bond [pyridyl pyrazole, pyridyl pyrrole, azaindole, pyridyl indole, pyrroloquinoline, and an analogue of the Blue Fluorescent Protein (BFP) chromophore] with the help of quantum mechanical calculations. For pyridyl pyrazoles, simulated spectra are used to help the interpretation of experimental ones and the effects of several substituents are investigated. Then it is shown that Time-Dependent Density Functional Theory fails to satisfactorily describe the energetic aspects of ESIPT for the BFP chromophore analogue. Equation-of-Motion Coupled Cluster theory is thus used to reach accurate insights for this challenging case.

Evaluation of reduced point charge models of proteins through Molecular Dynamics simulations: application to the Vps27 UIM-1-Ubiquitin complex.

Reduced point charge models of amino acids are designed, (i) from local extrema positions in charge density distribution functions built from the Poisson equation applied to smoothed molecular electrostatic potential (MEP) functions, and (ii) from local maxima positions in promolecular electron density distribution functions. Corresponding charge values are fitted versus all-atom Amber99 MEPs. To easily generate reduced point charge models for protein structures, libraries of amino acid templates are built. The program GROMACS is used to generate stable Molecular Dynamics trajectories of an Ubiquitin-ligand complex (PDB: 1Q0W), under various implementation schemes, solvation, and temperature conditions. Point charges that are not located on atoms are considered as virtual sites with a nul mass and radius. The results illustrate how the intra- and inter-molecular H-bond interactions are affected by the degree of reduction of the point charge models and give directions for their implementation; a special attention to the atoms selected to locate the virtual sites and to the Coulomb-14 interactions is needed. Results obtained at various temperatures suggest that the use of reduced point charge models allows to probe local potential hyper-surface minima that are similar to the all-atom ones, but are characterized by lower energy barriers. It enables to generate various conformations of the protein complex more rapidly than the all-atom point charge representation.

A Solvent-Mediated Coarse-Grained Model of DNA Derived with the Systematic Newton Inversion Method.

We present a new class of coarse-grained (CG) force fields (FFs) for B-DNA with explicit ions suited for large-scale mesoscale simulations at microsecond-micrometer scale using a wide spectrum of particle simulation methods from molecular dynamics to dissipative particle dynamics. The effective solvent-mediated pairwise interactions making up the FFs are obtained by inverting radial distribution functions and other particle-particle distributions obtained from all-atom simulations of numbers of octadecamer DNA fragments from the Ascona B-DNA library. The inverse Monte Carlo (IMC) method, later known as Newton inversion (NI) (Lyubartsev, A. P.; Laaksonen, A. Phys. Rev. E, 1995, 52, 3730-3737), was used together with the iterative Boltzmann inversion (IBI) scheme to compute the effective CG potentials. We show that this systematic structure-based approach is capable of providing converged potentials that accurately reproduce the structural features of the underlying atomistic system within a few percents of relative difference. We also show that a simple one-site-per-nucleotide model with 10 intramolecular pair interaction potentials is able to reproduce key features of DNA, for example, the persistence length and its dependence on the ionic concentration, experimentally determined around 50 nm at physiological salt concentration.

Rough Set Theory as an Interpretable Method for Predicting the Inhibition of Cytochrome P450 1A2 and 2D6.

Early prediction of ADME properties such as the cytochrome P450 (CYP) mediated drug-drug interactions is an important challenge in the drug discovery area. In this study, we propose to couple an original data mining approach based on Rough Set Theory (RST) to a structural description of molecules. The latter was achieved by using two types of structural keys: (1) the MACCS keys and (2) a set of five in-house fingerprints based on properties of the electron density distributions of chemical groups. The compounds considered are involved in the inhibition of CYP1A2 and CYP2D6. RST allowed the extraction of rules further used as classifiers to predict the inhibitory profile of an independent set of molecules. The results reached prediction accuracies of 90.6 and 88.2 % for CYP1A2 and CYP2D6, respectively. In addition, these classifiers were analyzed to determine which structural fragments were most used for building the rules, revealing relationships between the occurrence of particular molecular fragments and CYP inhibition. The results assessed RST as a suitable tool to build strongly predictive models and infer structure-activity rules associated with potency.

Charge density distributions derived from smoothed electrostatic potential functions: design of protein reduced point charge models.

To generate reduced point charge models of proteins, we developed an original approach to hierarchically locate extrema in charge density distribution functions built from the Poisson equation applied to smoothed molecular electrostatic potential (MEP) functions. A charge fitting program was used to assign charge values to the so-obtained reduced representations. In continuation to a previous work, the Amber99 force field was selected. To easily generate reduced point charge models for protein structures, a library of amino acid templates was designed. Applications to four small peptides, a set of 53 protein structures, and four KcsA ion channel models, are presented. Electrostatic potential and solvation free energy values generated by the reduced models are compared with the corresponding values obtained using the original set of atomic charges. Results are in closer agreement with the original all-atom electrostatic properties than those obtained with a previous reduced model that was directly built from the smoothed MEP functions [Leherte and Vercauteren in J Chem Theory Comput 5:3279-3298, 2009].

Implementation of a protein reduced point charge model toward molecular dynamics applications.

A reduced point charge model was developed in a previous work from the study of extrema in smoothed charge density distribution functions generated from the Amber99 molecular electrostatic potential. In the present work, such a point charge distribution is coupled with the Amber99 force field and implemented in the program TINKER to allow molecular dynamics (MD) simulations of proteins. First applications to two polypeptides that involve α-helix and ß-sheet motifs are analyzed and compared to all-atom MD simulations. Two types of coarse-grained (CG)-based trajectories are generated using, on one hand, harmonic bond stretching terms and, on the other hand, distance restraints. Results show that the use of the unrestrained CG conditions are sufficient to preserve most of the secondary structure characteristics but restraints lead to a better agreement between CG and all-atom simulation results such as rmsd, dipole moment, and time-dependent mean square deviation functions.