1,720,965 research outputs found
Computational Methods and Models for Atomistic Simulations of Ion Hydration, Ion-Ligand Complexes, and Ion Transport in Channels
Full text linkIons are omnipresent in Nature and play significant roles in a large number of biological and nanotechnological applications. For example, the investigation of their coordination with ligands is a recurrent theme in the scientific literature, with special reference to catalytic activity, nucleic acid cleavage, and anticancer drug studies. Besides, in the context of biological channels, ions may generate various kinds of ionic currents crucial for human physiological activities, like movement and heartbeats. Over the past seventy years, numerous experimental and theoretical techniques have been developed to address several properties of ions in aqueous solutions and in interaction with proteins, such as ion coordination, hydration free energy, ligand exchange times, and ionic currents in biochannels. In this regard, molecular dynamics (MD) simulations have proved very fruitful in providing a deep atomistic understanding of both complex and subtle phenomena involving ions. In this dissertation, novel computational approaches and applications are presented aiming at a better comprehension of different aspects of ion microsolvation, ion-ligand complex formation, and ion transport into protein channels, thus extending the range of available in silico techniques in this research area. The dissertation is structured into three parts. The first part of this thesis introduces a new computational methodology for analyzing the structural, thermodynamic, and kinetic properties of ion microsolvation, particularly effective in studying aqua-ion complex formation and solvent exchange in the first hydration shell, beyond the reach of standard MD simulations. The second part enhances the accuracy of force fields for ion-carboxylate interactions and subsequently presents a computational procedure for assessing stability constants and ligand exchange rates. This procedure, adaptable to different ions and ligands, shows promise in elucidating ion-ligand exchange mechanisms and predicting dissociation rates up to seconds, thus expanding applications of the method to more complex systems. The third part firstly discusses software developed for analyzing pore morphology and ion translocation pathways, and secondly the use of MD simulations and master-equations for the Kv4.3 potassium channel. In the latter, both techniques combined proved to be useful tools coupled with experiments to disclose the molecular causes of detrimental point mutations of the Kv4.3 potassium channel. Although the application areas of the above studies may appear diverse, each research work contributes consistently to a deeper understanding of the underlying molecular mechanisms characterizing ion solutions and strives to align computational models with experimental conditions, thus pushing the boundaries of the in silico research in this domain
Charge-Flow Profiles along Curvilinear Paths: A Flexible Scheme for the Analysis of Charge Displacement upon Intermolecular Interactions
Full text linkThe Charge-Displacement (CD) analysis has proven to be a powerful tool for a quantitative characterization of the electron-density flow occurring upon chemical bonding along a suitably chosen interaction axis. In several classes of interesting intermolecular interactions, however, an interaction axis cannot be straightforwardly defined, and the CD analysis loses consistency and usefulness. In this article, we propose a general, flexible reformulation of the CD analysis capable of providing a quantitative view of the charge displacement along custom curvilinear paths. The new scheme naturally reduces to ordinary CD analysis if the path is chosen to be a straight line. An implementation based on a discrete sampling of the electron densities and a Voronoi space partitioning is described and shown in action on two test cases of a metal-carbonyl and a pyridine-ammonia complex
Stochastic Model of Solvent Exchange in the First Coordination Shell of Aqua Ions
Full text link[Image: see text] Ion microsolvation is a basic, yet fundamental, process of ionic solutions underlying many relevant phenomena in either biological or nanotechnological applications, such as solvent reorganization energy, ion transport, catalytic activity, and so on. As a consequence, it is a topic of extensive investigations by various experimental techniques, ranging from X-ray diffraction to NMR relaxation and from calorimetry to vibrational spectroscopy, and theoretical approaches, especially those based on molecular dynamics (MD) simulations. The conventional microscopic view of ion solvation is usually provided by a “static” cluster model representing the first ion–solvent coordination shell. Despite the merits of such a simple model, however, ion coordination in solution should be better regarded as a complex population of dynamically interchanging molecular configurations. Such a more comprehensive view is more subtle to characterize and often elusive to standard approaches. In this work, we report on an effective computational strategy aiming at providing a detailed picture of solvent coordination and exchange around aqua ions, thus including the main structural, thermodynamic, and dynamic properties of ion microsolvation, such as the most probable first-shell complex structures, the corresponding free energies, the interchanging energy barriers, and the solvent-exchange rates. Assuming the solvent coordination number as an effective reaction coordinate and combining MD simulations with enhanced sampling and master-equation approaches, we propose a stochastic model suitable for properly describing, at the same time, the thermodynamics and kinetics of ion–water coordination. The model is successfully tested toward various divalent ions (Ca(2+), Zn(2+), Hg(2+), and Cd(2+)) in aqueous solution, considering also the case of a high ionic concentration. Results show a very good agreement with those issuing from brute-force MD simulations, when available, and support the reliable prediction of rare ion–water complexes and slow water exchange rates not easily accessible to usual computational methods
Simulating Metal Complex Formation and Ligand Exchange: Unraveling the Interplay between Entropy, Kinetics, and Mechanisms on the Chelate Effect
Full text linkMetal coordination is ubiquitous in Nature and central in many applications, ranging from nanotechnology to catalysis and environmental chemistry. Complex formation results from the subtle interplay between different thermodynamic, kinetic, and mechanistic contributions, which remain largely elusive to standard experimental methodologies and challenging for typical modeling approaches. Here, considering some prototypical metal complexes between Cd(II) and Ni(II) with various amine ligands, we present a comprehensive atomistic-level description of their chemical equilibrium, complex formation, and ligand exchange dynamics in aqueous solution, providing an excellent agreement with available association constants and formation rates spanning several orders of magnitude. This is achieved through an effective molecular simulation approach that combines finely tuned interatomic potentials with state-of-the-art enhanced sampling and kinetics techniques. Worthy of note, the nature of the chelate effect, a fundamental concept in coordination chemistry, is fully unravelled through the comparative analysis of the ligand binding reactions of monodentate and bidentate ligands in octahedral complexes. Results provide a complete picture illustrating all the concurrent contributions to this phenomenon, such as entropy, dissociation rates, and ligand binding mechanisms, in some cases contradicting previously held beliefs. This study represents a step forward for the in silico design and applications of coordination complex systems
Thermodynamics of Metal–Acetate Interactions
No full textMetal ions play crucial roles in protein- and ligand-mediated interactions. They not only act as catalysts to facilitate biological processes but are also important as protein structural elements. Accurately predicting metal ion interactions in computational studies has always been a challenge, and various methods have been suggested to improve these interactions. One such method is the 12-6-4 Lennard-Jones (LJ)-type nonbonded model. Using this model, it has been possible to successfully reproduce the experimental properties of metal ions in aqueous solution. The model includes induced dipole interactions typically ignored in the standard 12-6 LJ nonbonded model. In this we expand the applicability of this model to metal ion-carboxylate interactions. Using 12-6-4 parameters that reproduce the solvation free energies of the metal ions leads to an overestimation of metal ion-acetate interactions, thus, prompting us to fine-tune the model to specifically handle the latter. We also show that the standard 12-6 LJ model significantly falls short in reproducing the experimental binding free energy between acetate and 11 metal ions (Ni(II), Mg(II), Cu(II), Zn(II), Co(II), Cu(I), Fe(II), Mn(II), Cd(II), Ca(II), and Ag(I)). In this study, we describe optimized C4 parameters for the 12-6-4 LJ nonbonded model to be used with three widely employed water models (Transferable Intermolecular Potential with 3 Points (TIP3P), Simple Point Charge Extended (SPC/E), and Optimal Point Charge (OPC) water models). These parameters can accurately match the experimental binding free energy between 11 metal ions and acetate. These parameters can be applied to the study of metalloproteins and transition metal ion channels and transporters, as acetate serves as a representative of the negatively charged amino acid side chains from aspartate and glutamate
Unprecedented “Off‐Pathway” [2+2] Cycloaddition‐Retroelectrocyclization Reaction between an Unsymmetric Alkyne and Tetracyanoquinodimethane
Full text linkIn recent years, the [2+2] cycloaddition-retroelectrocyclization (CA-RE) reaction between electron-rich alkynes and electron-deficient alkenes has emerged as one of the most effective synthetic routes to prepare a large variety of molecular and polymeric electron donor-acceptor systems. Besides its simplicity, fast rate, and high yield, this reaction may also display complete and predictable regioselectivity, as for the case when tetracyanoquinodimethane (TCNQ) is used in combination with unsymmetric, activated alkynes. Here, we report the first example of a [2+2] CA-RE reaction between TCNQ and an aniline-activated alkyne following an "inverted" regiochemistry, thus leading to the exclusive formation of an unexpected regioisomer in contrast to the expected one. A combined experimental and theoretical study helped us to unravel the peculiar reaction mechanism underlying the regioselectivity switching
Simulating Metal-Imidazole Complexes
Full text linkOne commonly observed binding motif in metalloproteins involves the interaction between a metal ion and histidine’s imidazole side chains. Although previous imidazole-M(II) parameters established the flexibility and reliability of the 12-6-4 Lennard-Jones (LJ)-type nonbonded model by simply tuning the ligating atom’s polarizability, they have not been applied to multiple-imidazole complexes. To fill this gap, we systematically simulate multiple-imidazole complexes (ranging from one to six) for five metal ions (Co(II), Cu(II), Mn(II), Ni(II), and Zn(II)) which commonly appear in metalloproteins. Using extensive (40 ns per PMF window) sampling to assemble free energy association profiles (using OPC water and standard HID imidazole charge models from AMBER) and comparing the equilibrium distances to DFT calculations, a new set of parameters was developed to focus on energetic and geometric features of multiple-imidazole complexes. The obtained free energy profiles agree with the experimental binding free energy and DFT calculated distances. To validate our model, we show that we can close the thermodynamic cycle for metal-imidazole complexes with up to six imidazole molecules in the first solvation shell. Given the success in closing the thermodynamic cycles, we then used the same extended sampling method for six other metal ions (Ag(I), Ca(II), Cd(II), Cu(I), Fe(II), and Mg(II)) to obtain new parameters. Since these new parameters can reproduce the one-imidazole geometry and energy accurately, we hypothesize that they will reasonably predict the binding free energy of higher-level coordination numbers. Hence, we did not extend the analysis of these ions up to six imidazole complexes. Overall, the results shed light on metal-protein interactions by emphasizing the importance of ligand-ligand interaction and metal-π-stacking within metalloproteins
One-step functionalization of mildly and strongly reduced graphene oxide with maleimide: an experimental and theoretical investigation of the Diels-Alder [4+2] cycloaddition reaction
No full text: For large-scale graphene applications, such as the production of polymer-graphene nanocomposites, exfoliated graphene oxide (GO) and its reduced form (rGO) are presently considered to be very suitable starting materials, showing enhanced chemical reactivity with respect to pristine graphene, in addition to suitable electronic properties (i.e., tunable band gap). Among other chemical processes, a suitable way to obtain surface decoration of graphene is through a direct one-step Diels-Alder (DA) reaction, e.g. through the use of dienophile or diene moieties. However, the feasibility and extent of decoration largely depends on the specific graphene microstructure that in the case of rGO sheets is not easy to control and generally presents a high degree of inhomogeneity owing to various on-plane functionalization (e.g., epoxide and hydroxyl groups) or in-plane lattice defects. In an effort to gain some insights into the covalent functionalization of variably reduced GO samples, we present a combined experimental and theoretical study on the DA cycloaddition reaction of maleimide, a dienophile functional unit well-suited for chemical conjugation of polymers and macromolecules. In particular, we considered both mildly and strongly reduced GOs. Using thermogravimetry, Raman and X-Ray photoelectron spectroscopy, and elemental analysis we show evidence of variable chemical reactivity of rGO as a function of the residual oxygen content. Moreover, from quantum mechanical calculations carried out at the DFT level on different graphene reaction sites, we provide a more detailed molecular view to interpret experimental findings and to assess the reactivity series of different graphene modifications
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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