Human indoleamine-2,3-dioxygenase 2 cofactor lability and low substrate affinity explained by homology modeling, molecular dynamics and molecular docking.

The human indoleamine-2,3-dioxygenase 2 (hIDO2) protein is growing of interest as it is increasingly implicated in multiple diseases (cancer, autoimmune diseases, COVID-19). However, it is only poorly reported in the literature. Its mode of action remains unknown because it does not seem to catalyze the reaction for which it is attributed: the degradation of the L-Tryptophan into N-formyl-kynurenine.

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 levels. The trajectories formed by the-dependent BCP locations are interpreted in terms of the intermolecular interactions occurring within the crystal arrangements.

Temporary Intermediates of L-Trp Along the Reaction Pathway of Human Indoleamine 2,3-Dioxygenase 1 and Identification of an Exo Site.

Protein dynamics governs most of the fundamental processes in the human body. Particularly, the dynamics of loops located near an active site can be involved in the positioning of the substrate and the reaction mechanism. The understanding of the functioning of dynamic loops is therefore a challenge, and often requires the use of a multi-disciplinary approach mixing, for example, crystallographic experiments and molecular dynamics simulations.

Structure and Dynamics of an Archeal Monoglyceride Lipase from as Revealed by Crystallography and In Silico Analysis.

The crystallographic analysis of a lipase from (PFL) previously annotated as a lysophospholipase revealed high structural conservation with other monoglyceride lipases, in particular in the lid domain and substrate binding pockets. In agreement with this observation, PFL was shown to be active on various monoacylglycerols. Molecular Dynamics (MD) studies performed in the absence and in the presence of ligands further allowed characterization of the dynamics of this system and led to a systematic closure of the lid compared to the crystal structure.

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.

Molecular Mechanism for the Self-Supported Synthesis of Graphitic Carbon Nitride from Urea Pyrolysis.

Quantum chemical calculations combined with kinetic Monte Carlo simulations are performed to decipher the kinetics for the one-pot synthesis of two-dimensional graphitic carbon nitride (-CN) from urea pyrolysis. Two mechanisms are considered, one involving ammelide as the intermediate compound and the other considering cyanuric acid. Different grid growing patterns are investigated, and the size, shape, and density of the grids as well as the number and position of the defects are evaluated.

Influence of the presence of the heme cofactor on the JK-loop structure in indoleamine 2,3-dioxygenase 1.

Indoleamine 2,3-dioxygenase 1 has sparked interest as an immunotherapeutic target in cancer research. Its structure includes a loop, named the JK-loop, that controls the orientation of the substrate or inhibitor within the active site. However, little has been reported about the crystal structure of this loop.

Investigation of bound and unbound phosphoserine phosphatase conformations through elastic network models and molecular dynamics simulations.

The human phosphoserine phosphatase (hPSP) catalyses the last step in the biosynthesis of L-serine. It involves conformational changes of the enzyme lid once the substrate, phosphoserine (PSer), is bound in the active site. Here, Elastic Network Model (ENM) is applied to the crystal structure of hPSP to probe the transition between open and closed conformations of hPSP.

Crystal structures and snapshots along the reaction pathway of human phosphoserine phosphatase.

The equilibrium between phosphorylation and dephosphorylation is one of the most important processes that takes place in living cells. Human phosphoserine phosphatase (hPSP) is a key enzyme in the production of serine by the dephosphorylation of phospho-L-serine. It is directly involved in the biosynthesis of other important metabolites such as glycine and D-serine (a neuromodulator).

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.

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 β-strands of protein CD2, connected via turn inducers.

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-O interaction parameters, or the coarse-grain (CG) SIRAH water description.

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.

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.

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.

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.

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.

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.

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 β-sheet motifs are analyzed and compared to all-atom MD simulations.

Coarse Point Charge Models For Proteins From Smoothed Molecular Electrostatic Potentials.

To generate coarse electrostatic models of proteins, we developed an original approach to hierarchically locate maxima and minima in smoothed molecular electrostatic potentials. A charge-fitting program was used to assign charges to the so-obtained reduced representations. Templates are defined to easily generate coarse point charge models for protein structures, in the particular cases of the Amber99 and Gromos43A1 force fields.

Can descriptors of the electron density distribution help to distinguish functional groups?

Our study is aimed at understanding the characteristics of functional group descriptors based on peaks of the electronic density distribution rho(->r) . The descriptors calculated are the rho(->r) value at peak location, volume, ellipticity, curvatures of rho ( r) , and the peak-functional group distance. By the implementation of an automated and global process for large-scale calculation of the descriptors, we generated a statistically meaningful data set focusing on the association between peaks and 77 types of functional groups extracted from 62,936 organic molecules issued from the Cambridge Structural Database.

Collective motions of rigid fragments in protein structures from smoothed electron density distributions.

In this work, the Gaussian Network Model (GNM) and Anisotropic Network Model (ANM) approaches are applied to describe the dynamics of protein structure graphs built from calculated promolecular electron density (ED) distribution functions. A first set of analyses is carried out on results obtained from ED maxima calculated at various smoothing levels. A second set is achieved for ED networks whose edges are weighted by ED overlap integral values.

Structural, energetic, and dynamical properties of rotaxanes constituted of alpha-cyclodextrins and an azobenzene chain.

The [3]rotaxane synthesised as a single isomer constituted of two cyclodextrins (CDs) and an azobenzene chain [M.R. Craig, T.

Similarity measures based on Gaussian-type promolecular electron density models: alignment of small rigid molecules.

Various molecular similarity measures (overlap, Coulomb, kinetic, electrostatic energy) and similarity indices (Carbó, Hodgkin-Richards, Kulczynski, Shape Tanimoto) are applied to the superposition of 3D promolecular electron density (PED) distributions. The original aspect of the paper lies in the consideration of smoothed PEDs, which allow to decrease the number of local solutions to a superposition problem, together with the use of the less common kinetic and electrostatic energy similarity measures. Results are obtained for a family of five rigid endothiapepsin ligands that were already considered in previous applications, based on graph representations of their PED.

Influence of conformation on the representation of small flexible molecules at low resolution: alignment of endothiapepsin ligands.

In this contribution, we discuss a molecular representation mode for the generation of reduced descriptions of flexible molecules in various conformations. The representations of the endothiapepsin ligands are constituted by graphs of peaks obtained through a hierarchical merging algorithm which combines the location of promolecular electron density (ED) maxima with the decomposition of the molecular structures into fragments. The representations are then aligned through the use of a Monte Carlo/Simulated Annealing procedure.