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Structural properties of 2-butanol aqueous solutions at different concentrations have been studied using small- and wide-angle X-ray scattering and molecular dynamics simulations. The experimental structure factors have been accurately reproduced by the simulations, allowing one to explain their variation with concentration and to achieve a detailed description of the structural and dynamic properties of the studied systems. The analysis of experimental and computational data has shown that 2-butanol, the simplest aliphatic chiral alcohol, tends to form aggregates at a concentration above 1 M, affecting also both the structural and dynamic properties of the solvent.

Hypothesis The study of Amorphous Calcium Phosphate (ACP) has become a hot topic due to its relevance in living organisms and as a material for biomedical applications. The preparation and characterization of Mg-substituted ACP nanoparticles (AMCP) with tunable Ca/Mg ratio is reported in the present study to address the effect of Mg2+ on their structure and stability. Experiments AMCPs particles were synthesized by precipitation of the precursors from aqueous solutions. The particles were analyzed in terms of morphology, crystallinity, and thermal stability, to get a complete overview of their physico-chemical characteristics. Computational methods were also employed to simulate the structure of ACP clusters at different levels of Mg2+ substitution. Findings Our results demonstrate that AMCP particles with tunable composition and crystallinity can be obtained. The analysis of the heat-induced crystallization of AMCP shows that particles’ stability depends on the degree of Mg2+ substitution in the cluster, as confirmed by computational analyses. The presented results shed light on the effect of Mg2+ on ACP features at different structural levels and may be useful guidelines for the preparation and design of AMCP particles with a specific Ca/Mg ratio.

A water-soluble ruthenium(II) complex (L), capable of producing singlet oxygen (

A detailed understanding and interpretation of absorption spectra of molecular systems, especially in condensed phases, requires computational models that allow their structural and electronic features to be connected to the observed macroscopic spectra. This work is focused on modeling the electronic absorption spectrum of a fluorescent probe, namely, the 9-(4-((bis(2-((2-(ethylthio)ethyl)thio)ethyl)amino)methyl)phenyl)-6-(pyrrolidin-1-yl)-3

We describe a step-by-step protocol for the computation of relative dissociation free energy with GROMACS, based on a novel bidirectional nonequilibrium alchemical approach. The proposed methodology does not require any intervention on the code and allows to compute with good accuracy the RBFE between small molecules with arbitrary differences in volume, charge and Tanimoto index. The procedure is illustrated for the challenging SAMPL9 batch on the tutorial https://procacci.github.io/vdssb_gromacs/NE-RDFE/

In the context of drug-receptor binding affinity calculations using molecular dynamics techniques, we implemented a combination of Hamiltonian replica exchange (HREM) and a novel nonequilibrium alchemical methodology, called virtual double-system single-box, with increased accuracy, precision, and efficiency with respect to the standard nonequilibrium approaches. The method has been applied for the determination of absolute binding free energies of 16 newly designed noncovalent ligands of the main protease (3CLpro) of SARS-CoV-2. The core structures of 3CLpro ligands were previously identified using a multimodal structure-based ligand design in combination with docking techniques. The calculated binding free energies for four additional ligands with known activity (either for SARS-CoV or SARS-CoV-2 main protease) are also reported. The nature of binding in the 3CLpro active site and the involved residues besides the CYS-HYS catalytic dyad have been thoroughly characterized by enhanced sampling simulations of the bound state. We have identified several noncongeneric compounds with predicted low micromolar activity for 3CLpro inhibition, which may constitute possible lead compounds for the development of antiviral agents in Covid-19 treatment.

We developed a novel force field in the context of AMBER parameterization for glutamate and aspartate zinc(II)-binding residues. The interaction between the zinc ion and the coordinating atoms is represented by a spherical nonbonded parameterization. The polarization effect due to the zinc ion has been taken into account by redefining the atomic charges on the residues through accurate quantum mechanical calculations. The new zinc-binding ASP and GLU residues, along with the CYS and HIS zinc-binding residues, parameterized in a recent work [MacchiagodenaM.;J. Chem. Inf. Model.2019, 59, 3803−381631385702], allow users to reliably simulate 96% of the Zn-proteins available in the Protein Data Bank. The upgraded force field for zinc(II)-bound residues has been tested performing molecular dynamics simulations with an explicit solvent and comparing the structural information with experimental data for five different proteins binding zinc(II) with GLU, ASP, HIS, and CYS. We further validated our approach by evaluating the binding free energy of (R)-2-benzyl-3-nitropropanoic acid to carboxypeptidase A using a recently developed nonequilibrium alchemical method. We demonstrated that in this setting it is crucial to take into account polarization effects also on the metal-bound inhibitor.

Classical molecular dynamics (MD) simulations are widely used to inspect the behavior of zinc(II)-proteins at the atomic level, hence the need to properly model the zinc(II) ion and the interaction with its ligands. Different approaches have been developed to represent zinc(II) sites, with the bonded and nonbonded models being the most used. In the present work, we tested the well-known zinc AMBER force field (ZAFF) and a recently developed nonbonded force field (NBFF) to assess how accurately they reproduce the dynamic behavior of zinc(II)-proteins. For this, we selected as benchmark six zinc-fingers. This superfamily is extremely heterogenous in terms of architecture, binding mode, function, and reactivity. From repeated MD simulations, we computed the order parameter (S2) of all backbone N-H bond vectors in each system. These data were superimposed to heteronuclear Overhauser effect measurements taken by NMR spectroscopy. This provides a quantitative estimate of the accuracy of the FFs in reproducing protein dynamics, leveraging the information about the protein backbone mobility contained in the NMR data. The correlation between the MD-computed S2 and the experimental data indicated that both tested FFs reproduce well the dynamic behavior of zinc(II)-proteins, with comparable accuracy. Thus, along with ZAFF, NBFF represents a useful tool to simulate metalloproteins with the advantage of being extensible to diverse systems such as those bearing dinuclear metal sites.

A general approach enforcing nonperiodic boundary conditions for the computation of spectroscopic properties in solution has been improved including an effective description of charge-transfer contributions and coordination number adjustment for explicit solvent molecules. Both contributions are obtained from a continuous description of intermolecular hydrogen bonds, which has been employed also for an effective clustering of molecular dynamics trajectories. Fine tuning of the model has been performed for several water clusters, and then its efficiency and reliability have been demonstrated by computing the absorption spectra of different creatinine tautomers in aqueous solution.

Self assembled ordered structures, such as H- or J- type molecular aggregates of organic chromophores, are extremely interesting materials for different optoelectronic applications. In this work we present a novel characterization of light harvesting nanotubes formed by self-assembling of amphiphilic cyanine dyes in water, through a combined ultrafast spectroscopic and theoretical approach. In the condition of low inhomogeneous disorder at low temperature, broadband transient absorption spectroscopy revealed the presence of an unusual ultrafast behavior of the aggregate, manifested through intense and peculiar oscillations of the kinetic traces, lasting tens of picoseconds. Theoretical simulations were performed by adapting a model which grasps vibronically coherent effects in the double wall nanotube system experiencing inter-wall energy transfer. Good agreement between model predictions and experimental observations were obtained under the assumption of coupling between bright and dark electronic states. The model clarified the vibronic origin of the observed oscillations, evidencing new important pieces of information about transport mechanisms and excitonic interactions in these complex molecular systems.

The ethanol electro-oxidation catalyzed by Pd in an alkaline environment involves several intermediate reaction steps promoted by the hydroxyl radical, OH. In this work, we report on the dynamical paths of the first step of this oxidation reaction, namely the hydrogen atom abstraction CH3CH2OH + OH -> CH3CHOH + H2O, occurring at the Pd(111) surface and address the thermodynamic stability of the adsorbed reactants by means of quantum and molecular mechanics calculations, with special focus on the effect of the solvent. We have found that the impact of the solvent is significant for both ethanol and OH, contributing to a decrease in their adsorption free energies by a few dozen kcal mol-1 with respect to the adsorption energy under vacuum. Furthermore, we observe that hydrogen atom abstraction is enhanced for those simulation paths featuring large surface-reactant distances, namely, when the reactants weakly interact with the catalyst. The picture emerging from our study is therefore that of a catalyst whose coverage in an aqueous environment is largely dominated by OH with respect to ethanol. Nevertheless, only a small amount of them, specifically those weakly bound to the catalyst, is really active in the ethanol electro-oxidation reaction. These results open the idea of a rational design of co-catalysts based on the tuning of surface chemical properties to eventually enhance exchange current density.

Grimme's dispersion-corrected density functional theory (DFT-D) methods have emerged among the most practical approaches to perform accurate quantum mechanical calculations on molecular systems ranging from small clusters to microscopic and mesoscopic samples, i.e., including hundreds or thousands of molecules. Moreover, DFT-D functionals can be easily integrated into popular ab initio molecular dynamics (MD) software packages to carry out first-principles condensed-phase simulations at an affordable computational cost. Here, starting from the well-established D3 version of the dispersion-correction term, we present a simple protocol to improve the accurate description of the intermolecular interactions of molecular clusters of growing size, considering acetonitrile as a test case. Optimization of the interaction energy was performed with reference to diffusion quantum Monte Carlo calculations, successfully reaching the same inherent accuracy of the latter (statistical error of ∼0.1 kcal/mol per molecule). The refined DFT-D3 model was then used to perform ab initio MD simulations of liquid acetonitrile, again showing significant improvements toward available experimental data with respect to the default correction.

5-Nitroimidazole (5NIMH), chosen as a molecular model of nitroimidazole derivatives, which represent a broad-spectrum class of antimicrobials, was incorporated into the ruthenium complexes [Ru(tpy)(phen)(5NIM)]PF6 (1) and [Ru(tpy)(dmp)(5NIM)]PF6 (2) (tpy = terpyridine, phen = phenanthroline, dmp = 2,9-dimethyl-1,10-phenanthroline). Besides the uncommon metal coordination of 5-nitroimidazole in its imidazolate form (5NIM), the different architectures of the spectator ligands (phen and dmp) were exploited to tune the "mode of action" of the resulting complexes, passing from a photostable compound where the redox properties of 5NIMH are preserved (1) to one suitable for the nitroimidazole phototriggered release (2) and whose antibacterial activity against B. subtilis, chosen as cellular model, is effectively improved upon light exposure. This study may provide a fundamental knowledge on the use of Ru(II)-polypyridyl complexes to incorporate and/or photorelease biologically relevant nitroimidazole derivatives in the design of a novel class of antimicrobials.

Water has a fundamental role in important processes spanning a wide range of pressure and temperature conditions. Knowledge of structural, dynamic and thermodynamic properties of water at nonstandard conditions is a primary concern since interest in astronomical, geological, and technological processes is continuously growing. Molecular dynamics simulations allow us to study thermodynamic conditions that require sophisticated techniques and instruments, while at the same time offering the interpretation of properties at the atomic level. It is established that the behavior of water is strongly affected by the temperature and pressure conditions, determining the existence of low and high density regimes. For the first time, a thermodynamic property, isothermal compressibility, has been adopted to detect the low-high density turning point at ambient temperature in liquid water due to pressure. Molecular dynamics simulations have been performed with five three-site models, allowing us to characterize the complexity of water nature at these conditions at the atomic level.

The complete path of the Brandi-Guarna rearrangement of 5-spirocyclopropane isoxazolidines has been investigated by means of density functional theory calculations to rationalize the competing formation of tetrahydropyridones and enaminones by the determination of the minimum energy reaction paths. Our calculations confirm that the rearrangement is triggered by the homolysis of the isoxazolidine N-O bond followed by cleavage of one of the two C-CH2 cyclopropane bonds as previously proposed by the Fabian group [ Eur. J. Org. Chem. 2001, 2001, 4223]. In addition, the results of this work suggest that in the presence of a stereogenic center at isoxazolidine C-4', the formation of a piperidinone or an enaminone as the final product depends on which of the two diastereotopic C-CH2 bonds of cyclopropane is cleaved in the second step of the process. The result can be of great interest for the understanding of other processes involving the opening of a cyclopropane ring.

The structural and vibrational properties of the molecular units of sulfur hexafluoride crystal as a function of pressure have been studied by the Extreme Pressure Polarizable Continuum Model (XP-PCM) method. Within the XP-PCM model, single molecule calculations allow a consistent interpretation of the experimental measurements when considering the effect of pressure on both the molecular structure and the vibrational normal modes. This peculiar aspect of XP-PCM provides a detailed description of the electronic origin of normal modes variations with pressure, via the curvature of the potential energy surface and via the anharmonicity of the normal modes. When applied to the vibrational properties of the sulfur hexafluoride crystal, the XP-PCM method reveals a hitherto unknown interpretation of the effects of the pressure on the vibrational normal modes of the molecular units of this crystal.

We have studied the non-covalent interaction between PF-07321332 and SARS-CoV-2 main protease at the atomic level using a computational approach based on extensive molecular dynamics simulations with explicit solvent. PF-07321332, whose chemical structure has been recently disclosed, is a promising oral antiviral clinical candidate with well-established anti-SARS-CoV-2 activity in vitro. The drug, currently in phase III clinical trials in combination with ritonavir, relies on the electrophilic attack of a nitrile warhead to the catalytic cysteine of the protease. Nonbonded interaction between the inhibitor and the residues of the binding pocket, as well as with water molecules on the protein surface, have been characterized using two different force fields and the two possible protonation states of the main protease catalytic dyad HIS41-CYS145. When the catalytic dyad is in the neutral state, the non-covalent binding is likely to be stronger. Molecular dynamics simulations seems to lend support for an inhibitory mechanism in two steps: a first non-covalent addition with the dyad in neutral form and then the formation of the thiolate-imidazolium ion pair and the ligand relocation for finalising the electrophilic attack., Graphical abstract Image 1

The study of Amorphous Calcium Phosphate (ACP) has become a hot topic due to its relevance in living organisms and as a material for biomedical applications. The preparation and characterization of Mg-substituted ACP nanoparticles (AMCP) with tunable Ca/Mg ratio is reported in the present study to address the effect of MgAMCPs particles were synthesized by precipitation of the precursors from aqueous solutions. The particles were analyzed in terms of morphology, crystallinity, and thermal stability, to get a complete overview of their physico-chemical characteristics. Computational methods were also employed to simulate the structure of ACP clusters at different levels of MgOur results demonstrate that AMCP particles with tunable composition and crystallinity can be obtained. The analysis of the heat-induced crystallization of AMCP shows that particles' stability depends on the degree of Mg

The regioselectivity in the 1,3-dipolar cycloaddition (1,3-DC) between five-membered cyclic nitrone and methylenecyclopropane (MCP) has been studied through density functional theory (DFT) calculations. The computational study of 1,3-DC with different 1-alkyl- (or 1,1-dialkyl)-substituted alkenes and the comparison with MCP have evidenced that the electrostatic interaction has a central role in the regioselectivity of the reactions. It has been observed that the electronic effect of the substituent (donor or attractor groups) determines the polarization of the alkene double bond and the reaction mechanism, consequently determining the interaction with nitrones and favoring an orientation between this moiety and the dipolarophile.

This work proposes a voltammetric aptasensor to detect deoxynivalenol (DON) mycotoxin. The development steps of the aptasensor were partnered for the first time to a computational study to gain insights onto the molecular mechanisms involved into the interaction between a thiol-tethered DNA aptamer (80mer-SH) and DON. The exploited docking study allowed to find the binding region of the oligonucleotide sequence and to determine DON preferred orientation. A biotinylated oligonucleotide sequence (20mer-BIO) complementary to the aptamer was chosen to carry out a competitive format. Graphite screen-printed electrodes (GSPEs) were electrochemically modified with polyaniline and gold nanoparticles (AuNPs@PANI) by means of cyclic voltammetry (CV) and worked as a scaffold for the immobilization of the DNA aptamer. Solutions containing increasing concentrations of DON and a fixed amount of 20mer-BIO were dropped onto the aptasensor surface: the resulting hybrids were labeled with an alkaline phosphatase (ALP) conjugate to hydrolyze 1-naphthyl phosphate (1-NPP) substrate into 1-naphthol product, detected by differential pulse voltammetry (DPV). According to its competitive format, the aptasensor response was signal-off in the range 5.0-30.0 ng.mL(-1) DON. A detection limit of 3.2 ng.mL(-1) was achieved within a 1-hour detection time. Preliminary experiments on maize flour samples spiked with DON yielded good recovery values. (C) 2020 Elsevier B.V. All rights reserved.

The presence of ions induces perturbations in the water network, these structural and dynamic modifications can extent over space scales overcoming the local solvation shell: aqueous solutions of sodium perchlorate (NaClO4) are characterized by extended phenomena of structure breaking of the solvent network. The aim of the present work is the experimental investigation of the interplay between the local structural modifications induced by the perchlorate ions and the collective dynamical properties of the solvent. Ultrafast Optical Kerr Effect (OKE) and time resolved infrared absorption are the experimental techniques adopted: OKE is mostly sensitive to the collective properties of the sample, while transient IR provides access to local properties of the solvent. Classical Molecular Dynamics (MD) simulations support the analysis of the experimental results. All experiments and simulations are performed at room temperature, varying the concentrations (0–6 M) and varying the applied pressure (10−4–1.3 GPa). Experiments and computer simulations confirm that pressure and concentration have convergent effects on the water dynamics, due to the analogous modification of the short-range liquid structure that cancel some dynamical anomalies typical of pure water. Both local and collective dynamic observables point to structural properties as responsible for their peculiar pressure and concentration dependence.

With the world plagued by the coronavirus pandemic, efficient automated protocols for a reliable in silico estimate of the binding strength of compounds vs SARS-CoV2-related biological targets are urgently needed. The consensus computational pipeline in drug development starts from triaging via docking tools of data-driven generated libraries of compounds followed by Molecular Dynamics (MD) techniques on a subset of the best scoring ligands. In this context, absolute binding free energy determination via MD is a crucial and challenging intermediate step, preceding the drug optimization process, using efficient alchemical MD techniques on strictly congeneric series. Here we describe an alchemical MD technique based on nonequilibrium thermodynamics capable of delivering in few hours on a modern HPC platform reliable estimates of the absolute binding free energies in drug–receptor systems. The methodology can be combined with well established alchemical relative binding free energy calculations providing an automatable workflow for drug optimization starting from a set of chemically distant ligands.

Robotics for Medicine and Healthcare is undoubtedly an important emerging sector of the newborn third millennium. There are many aspects in which this branch of robotics already operates; in this article, the focus will be on the so-called “Robotic assistive technology”. In particular, a novel electromechanical design for an assistive Hand Exoskeleton System is presented here. Since freedom of movement plays a crucial role in making actually usable an assistive device, the main point of innovation of the proposed solution lies in the complete wearability of the resulting system: including mechanics, control electronics, and power supply. From the combination of the authors’ previous experience with the improvements presented in this article comes a fully standalone tailor-made assistive device, https://youtu.be/MiF5Hn1Q3fA https://www.youtube.com/watch?v=KfjOP6QuUnk

Since the development of the first autonomous underwater vehicles, the demanded tasks for subsea operations have become more and more challenging as, for instance, intervention, maintenance and repair of seabed installations, in addition to surveys. As a result of these considerations, the development of Autonomous Underwater Re-configurable Vehicles (AURVs) with the capability of interacting with the surrounding environment and autonomously changing the configuration, according to the task at hand, can represent a real breakthrough in underwater system technologies. A novel formulation for the dynamic maneuverability analysis of an AURV, adapting Yoshikawa’s manipulability theory for robotic arms, is proposed., https://youtu.be/huq45_AmoAM

In recent years, seabed inspection has become one of the most sought-after tasks for Autonomous Underwater Vehicles (AUVs) in various applications. Forward-Looking Sonars (FLS) are commonly favored over optical cameras, which are not-negligibly affected by environmental conditions, to carry out inspection and exploration tasks. Indeed, sonars are not influenced by illumination conditions and can provide high-range data at the cost of lower-resolution images compared to optical sensors. However, due to the lack of features, sonar images are often hard to interpret by using conventional image processing techniques, leading to the necessity of human operators analyzing thousands of images acquired during the AUV mission to identify the potential targets of interest. This paper reports the development of an Automatic Target Recognition (ATR) methodology to identify and localize potential targets in FLS imagery, which could help human operators in this challenging, demanding task. The Mask R-CNN (Region-based Convolutional Neural Network), which constitutes the core of the proposed solution, has been trained with a dataset acquired in May 2019 at the Naval Support and Experimentation Centre (Centro di Supporto e Sperimentazione Navale - CSSN) basin, in La Spezia (Italy). The ATR strategy was then successfully validated online in the same site in October 2019, where the targets were replaced and relocated on the seabed.

Robotics for Medicine and Healthcare is undoubtedly an important emerging sector of the newborn third millennium. There are many aspects in which this branch of robotics already operates; in this article, the focus will be on the so-called “Robotic assistive technology”. In particular, a novel electromechanical design for an assistive Hand Exoskeleton System is presented here. Since freedom of movement plays a crucial role in making actually usable an assistive device, the main point of innovation of the proposed solution lies in the complete wearability of the resulting system: including mechanics, control electronics, and power supply. From the combination of the authors’ previous experience with the improvements presented in this article comes a fully standalone tailor-made assistive device.

We have applied a computational strategy, using a combination of virtual screening, docking and molecular dynamics techniques, aimed at identifying possible lead compounds for the non-covalent inhibition of the main protease 3CLpro of the SARS-CoV2 Coronavirus. Based on the X-ray structure (PDB code: 6LU7), ligands were generated using a multimodal structure-based design and then docked to the monomer in the active state. Docking calculations show that ligand-binding is strikingly similar in SARS-CoV and SARS-CoV2 main proteases. The most potent docked ligands are found to share a common binding pattern with aromatic moieties connected by rotatable bonds in a pseudo-linear arrangement.

The paper presents an accurate in silico measurement of the dissociation constant of HCQ on three important SARS-Cov2 protein targets, namely the main protease (3CLpro) and the Papain-like protease (PLpro) and the RNA dependent RNA polimerase (RdRp), using the recently the released PDB stuructures of these protein. Calculations are done using state-of-the art force fields and advanced simulation methodologies combining enhanced sampling and nonequilibrium techniques amenable to massive parallelization on a dedicated HPC cluster.We have shown that HCQ may act as a mild inhibitor for all the three viral proteins, with potency increasing in the series PLpro, 3CLpro, RdRp. By analyzing the bound state configurations, we were able to improve the potency for the 3CLpro target, designing a novel HCQ-inspired compound, named PMP329, with predicted nanomolar activity. If confirmed in vitro, our results provide a convincing molecular rationale for the use of HCQ or of strictly related derivatives in the treatment of Covid-19.

The role of Virtual Reality (VR) tools in molecular sciences is analyzed in this contribution through the presentation of the Caffeine software to the quantum chemistry community. Caffeine, developed at Scuola Normale Superiore, is specifically tailored for molecular representation and data visualization with VR systems, such as VR theaters and helmets. Usefulness and advantages that can be gained by exploiting VR are here reported, considering few examples specifically selected to illustrate different level of theory and molecular representation.