Solvent effects on catechol's binding affinity: investigating the role of the intra-molecular hydrogen bond through a multi-level computational approach.

The subtle interplay between the inter-molecular interactions established by catechol with the surrounding solvent and the intra-molecular hydrogen bond (HB) characterizing its conformational dynamics is investigated through a multi-level computational approach. First, quantum mechanical (QM) calculations are employed to accurately characterize both large portions of the catechol's potential energy surface and the interaction energy with neighboring solvent molecules. The acquired information is thereafter exploited to develop a QM derived force-field (QMD-FF), in turn employed in molecular dynamics (MD) simulations based on classical mechanics. The reliability of the QMD-FF is further validated through a comparison with the outcomes of ab initio molecular dynamics, also purposely carried out in this work. In agreement with recent experimental findings, the MD results reveal remarkable differences in the conformational behavior of isolated and solvated catechol, as well as among the investigated solvents, namely water, acetonitrile or cyclohexane. The rather strong intramolecular HB, settled between the vicinal phenolic groups and maintained in the gas phase, loses stability when catechol is solvated in polar solvents, and is definitively lost in protic solvents such as water. In fact, the internal energy increase associated with the rotation of one hydroxyl group and the breaking of the internal HB is well compensated by the intermolecular HB network available when both phenolic hydrogens point toward the surrounding solvent. In such a case, catechol is stabilized in a chelating conformation, which in turn could be very effective in water removal and surface anchoring. Besides unraveling the role of the different contributors that govern catechol's conformational dynamics, the QMD-FF developed in this work could be in future employed to model larger catechol containing molecules, due to its accuracy to reliably model both internal flexibility and solvent effects, while exploiting MD computational benefits to include more complex players as for instance surfaces, ions or biomolecules.

Chasing unphysical TD-DFT excited states in transition metal complexes with a simple diagnostic tool.

Transition Metal Complexes (TMCs) are known for the rich variety of their excited states showing different nature and degrees of locality. Describing the energies of these excited states with the same degree of accuracy is still problematic when using time-dependent density functional theory in conjunction with the most current density functional approximations. In particular, the presence of unphysically low lying excited states possessing a relevant Charge Transfer (CT) character may significantly affect the spectra computed at such a level of theory and, more relevantly, the interpretation of their photophysical behavior. In this work, we propose an improved version of the MAC index, recently proposed by the authors and collaborators, as a simple and computationally inexpensive diagnostic tool that can be used for the detection and correction of the unphysically predicted low lying excited states. The analysis, performed on five prototype TMCs, shows that spurious and ghost states can appear in a wide spectral range and that it is difficult to detect them only on the basis of their CT extent. Indeed, both delocalization of the excited state and CT extent are criteria that must be combined, as in the MAC index, to detect unphysical states.

Following the evolution of excited states along photochemical reaction pathways.

Analyzing the behavior of potential energy surfaces (PESs) of diabatic excited states (ESs) becomes of crucial importance for a complete understanding of complex photochemical reactions. Since the definition of a compact representation for the transition density matrix, the use of the natural transition orbitals (NTOs) has become a routine practice in time-dependent density functional theory calculations. Their popularity has remarkably grown due to its simple orbital description of electronic excitations. Indeed, very recently, we have presented a new formalism used for the optimization of ESs by tracking the state of interest computing the NTO's overlap between consecutive steps of the procedure. In this new contribution, we generalize the use of this NTO's overlap-based state-tracking formalism for the analysis of all the desired diabatic states along any chemical reaction pathway. Determining the PES of the different diabatic states has been automatized by developing an extension of our recently presented algorithm, the so-called SDNTO: "Steepest Descent minimization using NTOs." This automatized overlap-based procedure allows an agile and convenient analysis of the evolution of the ESs avoiding the intrinsic ambiguity of visualizing orbitals or comparing physical observables. The analysis of two photochemical reactions of the same nature with different PES landscapes perfectly illustrates the utility of this new tool.

Automated parameterization of quantum-mechanically derived force-fields including explicit sigma holes: A pathway to energetic and structural features of halogen bonds in gas and condensed phase.

In classical molecular dynamics, general purpose atomistic force-fields (FFs) often deliver inaccurate results when dealing with halogen bonds (XBs), notwithstanding their crucial role in many fields of science, ranging from material design to drug development. Given the large dimensions of the systems of interest, it would be therefore desirable to increase the FF accuracy maintaining the simplicity of the standard Lennard-Jones (LJ) plus point charge description to avoid an excessive computational cost. A simple yet effective strategy consists in introducing a number of virtual sites able to mimic the so-called "explicit σ-hole." In this work, we present an automated FF parameterization strategy based on a global optimization of both LJ and charge parameters with respect to accurate quantum mechanical data, purposely computed for the system under investigation. As a test case, we report on two homologue series, characterized either by weak or strong XBs, namely, the di-halogenated methanes and the mono-, di-, and tri-substituted acetonitriles, taking into consideration Cl, Br, and I substituents. The resulting quantum mechanically derived FFs are validated for each compound in the gas and in the condensed phase by comparing them to general purpose and specific FFs without virtual sites and to highly accurate reference quantum mechanical data. The results strongly support the adoption of the specific FFs with virtual sites, which overcome the other investigated models in representing both gas phase energetics and the structural patterns of the liquid phase structure related to the presence of XBs.

Excited state tracking during the relaxation of coordination compounds.

The ability to locate minima on electronic excited states (ESs) potential energy surfaces both in the case of bright and dark states is crucial for a full understanding of photochemical reactions. This task has become a standard practice for small- to medium-sized organic chromophores thanks to the constant developments in the field of computational photochemistry. However, this remains a very challenging effort when it comes to the optimization of ESs of transition metal complexes (TMCs), not only due to the presence of several electronic ESs close in energy, but also due to the complex nature of the ESs involved. In this article, we present a simple yet powerful method to follow an ES of interest during a structural optimization in the case of TMCs, based on the use of a compact hole-particle representation of the electronic transition, namely the natural transition orbitals (NTOs). State tracking using NTOs is unambiguously accomplished by computing the mono-electronic wave function overlap between consecutive steps of the optimization. Here, we demonstrate that this simple but robust procedure works not only in the case of the cytosine but also in the case of the ES optimization of a ruthenium nitrosyl complex which is very problematic with standard approaches. © 2019 The Authors. Journal of Computational Chemistry published by Wiley Periodicals, Inc.

Using density based indexes to characterize excited states evolution.

With the aim of offering new computational tools helping in the description of photochemical reactions and phenomena occurring at the excited state, we present in this work the capability of a density based index (Π) in locating decay channels from higher to lower excited states. The Π index, previously applied to disclose non-radiative decay channels from the first excited state to the ground state, is very simple in its formulation and can be evaluated, practically with no extra computational cost, and coupled to any quantum method able to provide excited states densities. Indeed, this index relies only on the knowledge of energetics and electron densities of the different electronic states involved in the decay. In the present work, we show the proficiency of the Π index in the general case of decay between excited states by applying it to two model systems well characterized both theoretically and experimentally. In both cases, this descriptor was successful in spotting the regions where excited states are more likely to decay, thus suggesting its potential interest for further application in the design of new compounds. © 2018 Wiley Periodicals, Inc.

Coupled hydroxyl and ether functionalisation in EAN derivatives: the effect of hydrogen bond donor/acceptor groups on the structural heterogeneity studied with X-ray diffractions and fixed charge/polarizable simulations.

We present a study by energy-dispersive X-ray diffraction of liquid 2-(2-hydroxyethoxy)ethan-1-ammonium nitrate, NH3CH2CH2(OCH2CH2OH)+NO3- (22HHEAN). This ionic liquid is derived from the parent ethylammonium nitrate (EAN) with an ether link in the chain and a hydroxyl group in the terminal position. The absence of peaks at low-q values in the experimental diffraction curve indicates that the added polar groups and the high conformational isomerism of the cations alter strongly the nanosegregation of the parent EAN liquid. Aggregation between ionic species may involve hydrogen bonding between cations and anions and a variety of intermolecular hydrogen bonds between cations. Diffraction patterns are compared with the results of molecular dynamics simulations with two different force fields: the fixed point charge force field (GAFF) with different charge scaling protocols and the polarizable AMOEBA force field. Most point charge models lead to the appearance of a quite evident low q-peak which decreases gradually, when the percentage and type of the scaling (uniform vs. non-uniform) are increased. In the polarisable model and in the model where only anion charges are scaled to 20%, instead, the pre-peak is absent in agreement with our experiments.

How are the charge transfer descriptors affected by the quality of the underpinning electronic density?

With the aim of investigating qualitatively and quantitatively the impact of using excited state relaxed or unrelaxed density for the estimation of nature and characteristic of electronic excited states, we analyzed the behavior of 52 exchange correlation functionals for the prediction of density-based indexes such as those recently introduced in literature to evaluate the charge transfer distance (DCT ) (Le Bahers et al. J. Chem. Theory Comput. 2011, 7, 2498) in the case of a prototype family of push-pull dyes. Our results show that while a qualitatively consistent assessment of the nature of the excited states is obtained using either the unrelaxed or the relaxed density, from a quantitative standpoint we observe large discrepancies in the charge transfer distance for electronic transitions having substantial CT character. This behavior is independent of nature of the exchange-correlation functional used. © 2018 Wiley Periodicals, Inc.

Using Density Based Indexes and Wave Function Methods for the Description of Excited States: Excited State Proton Transfer Reactions as a Test Case.

To provide tools to interpret photochemical reactions, in this paper we demonstrate how a recently developed density-based index (DCT), up to now used in conjunction with time dependent density functional theory methods, can be extended to multiconfigurational methods. This index can guide chemists in the interpretation of photochemical reactions providing a measure of the spatial extent of a photoinduced charge transfer and, more generally, of charge transfer phenomena. This qualitative and quantitative description can be particularly relevant in the case of multiconfigurational calculations providing a simple tool for the interpretation of their complex outputs. To prove the potentiality of this approach we have considered a simple intramolecular excited state proton transfer reaction as study case and applied both wave function (CASSCF-CASPT2) and density-based methods in conjunction with a DCT analysis. Our results confirm that, also in the case of multiconfigurational methods, the DCT provides very useful information about the structural reorganization of a molecule at the excited state.

Structure and dynamics of propylammonium nitrate-acetonitrile mixtures: An intricate multi-scale system probed with experimental and theoretical techniques.

In this article, we report the study of structural and dynamical properties for a series of acetonitrile/propylammonium nitrate mixtures as a function of their composition. These systems display an unusual increase in intensity in their X-ray diffraction patterns in the low-q regime, and their 1H-NMR diffusion-ordered NMR spectroscopy (DOSY) spectra display unusual diffusivities. However, the magnitude of both phenomena for mixtures of propylammonium nitrate is smaller than those observed for ethylammonium nitrate mixtures with the same cosolvent, suggesting that the cation alkyl tail plays an important role in these observations. The experimental X-ray scattering data are compared with the results of molecular dynamics simulations, including both ab initio studies used to interpret short-range interactions and classical simulations to describe longer range interactions. The higher level calculations highlight the presence of a strong hydrogen bond network within the ionic liquid, only slightly perturbed even at high acetonitrile concentration. These strong interactions lead to the symmetry breaking of the NO3- vibrations, with a splitting of about 88 cm-1 in the ν3 antisymmetric stretch. The classical force field simulations use a greater number of ion pairs, but are not capable of fully describing the longest range interactions, although they do successfully account for the observed concentration trend, and the analysis of the models confirms the nano-inhomogeneity of these kinds of samples.

Charge transfer excitations in TDDFT: A ghost-hunter index.

This work presents a new index, MAC , enabling the on-the-fly detection of ghost charge transfer (CT) states, a major problem in time-dependent density-functional theory calculations. This computationally inexpensive index, derived as a modification of the Mulliken estimation of transition energy for CT excitations, relies on two basic ingredients: an effective CT distance, computed using our density-based index (DCT ), and an orbital weighted estimation of the Ionization Potential and Electron Affinity. Some model systems, representative of both intermolecular and intramolecular CT excitations, were chosen as test cases. The robustness of our approach was verified by analyzing the behavior of functionals belonging to different classes (GGA, global hybrids and range separated hybrids). The results obtained show that ghost states are correctly spotted, also in the delicate case of intramolecular excitations displaying substantial donor-bridge-acceptor delocalization, in a regime for which the standard Mulliken formulation attends its limits. © 2017 Wiley Periodicals, Inc.

Unexpected proton mobility in the bulk phase of cholinium-based ionic liquids: new insights from theoretical calculations.

We have explored by means of ab initio molecular dynamics two ionic liquids based on the combination of a choline cation with deprotonated cysteine and aspartic acid anions. While the combination of the strong base choline with various other amino-acids leads to the formation of a highly ionized medium where proton transfer is negligible, the presence of additional protic functions on the SH and COOH groups leads to an unexpected and interesting behavior and to a sizable migration of their acidic protons onto the NH2 basic terminals. As far as we know this is the first time that such proton migration, which in water leads to the well-known zwitterionic form of aminoacids, is observed to take place in their ionized, anionic form. We analyze in detail such dynamical effects using accurate ab initio molecular dynamics computations validated through comparison with X-ray scattering data.

Theoretical study of ionic liquids based on the cholinium cation. Ab initio simulations of their condensed phases.

We have explored by means of ab initio molecular dynamics the homologue series of 11 different ionic liquids based on the combination of the cholinium cation with deprotonated amino acid anions. We present a structural analysis of the liquid states of these compounds as revealed by accurate ab initio computations of the forces. We highlight the persistent structural motifs that see the ionic couple as the basic building block of the liquid whereby a strong hydrogen bonding network substantially determines the short range structural behavior of the bulk state. Other minor docking features of the interaction network are also discovered and described. Special cases along the series such as Cysteine and Phenylalanine are discussed in the view of their peculiar properties due to zwitterion formation and additional long-range structural organization.

Two different models to predict ionic-liquid diffraction patterns: fixed-charge versus polarizable potentials.

This study reports the performance of classical molecular dynamics (MD) in predicting the X-ray diffraction patterns of butylammonium nitrate (BAN) and two derivatives, 4-hydroxybutan-1-ammonium nitrate (4-HOBAN) and 4-methoxybutan-1-ammonium nitrate (4-MeOBAN). The structure functions and radial distribution functions obtained from energy-dispersive X-ray diffraction spectra, recorded newly for BAN and for the first time for 4-MeOBAN and 4-HOBAN, are compared with the corresponding quantities calculated from MD trajectories, to access information on the morphology of these liquids. The different behavior of two force fields, a polarizable multipole force field and a fixed-charge one supplemented by an explicit three-body term, is shown. The three-body force field proves to be superior in reproducing the intermediate q range, for which the polarizable force field gives the wrong peak position and intensities. In addition, both models can correctly account for the presence or absence of a low q peak in the scattering patterns.

Cholinium-amino acid based ionic liquids: a new method of synthesis and physico-chemical characterization.

In the present work we report the synthesis and physico-chemical characterization in terms of the viscosity and density of a wide series of cholinium-amino acid based room temperature ionic liquids ([Ch][AA] RTILs). 18 different amino acids were used to obtain 14 room temperature ILs. Among the most common AAs, only valine did not form an RTIL but it is a liquid above 80 °C. With respect to the methods reported in the literature we propose a synthesis based on potentiometric titration which has several advantages such as shorter preparation time, stoichiometry within ±1%, very high yields (close to 100%), high reproducibility, and no use of organic solvents, thus being more environmentally friendly. We tried to prepare dianionic ILs with some AAs with two potentially ionisable groups but in all cases the salts were solids at room temperature. All the ILs were characterized by (1)H NMR to confirm the stoichiometry. Physico-chemical properties such as density, viscosity, refractive index and conductivity were measured as a function of temperature and correlated with empirical equations. The values were compared with the data already reported in the literature for some [Ch][AA] ILs. The thermal expansion coefficient αp and the molar volume Vm were also calculated from the experimental density values. Due to the high number of AAs explored and their structural heterogeneity we have been able to find some interesting correlations between the data obtained and the structural features of the AAs in terms of the alkyl chain length, hydrogen bonding ability, stacking and cyclization. Some parameters were also found to be in good agreement with those reported for other ILs. We think that these data can give an important contribution to the understanding of the structure-property relationship of ILs because they focused on the structural effect of the anions, while most data in the literature are focussed on the cations.

Structural studies on choline-carboxylate bio-ionic liquids by x-ray scattering and molecular dynamics.

We report a X-ray diffraction and molecular dynamics study on three choline-based bio-ionic liquids, choline formate, [Ch] [For], choline propanoate, [Ch][Pro], and choline butanoate, [Ch][But]. For the first time, this class of ionic liquids has been investigated by X-ray diffraction. Experimental and theoretical structure factors have been compared for each term of the series. Local structural organization has been obtained from ab initio calculations through static models of isolated ion pairs and dynamic simulations of small portions of liquids through twelve, ten, and nine ion pairs for [Ch][For], [Ch][Pro], and [Ch][But], respectively. All the theoretical models indicate that cations and anions are connected by strong hydrogen bonding and form stable ion pairs in the liquid that are reminiscent of the static ab initio ion pairs. Different structural aspects may affect the radial distribution function, like the local structure of ion pairs and the conformation of choline. When small portions of liquids have been simulated by dynamic quantum chemical methods, some key structural features of the X-ray radial distribution function were well reproduced whereas the classical force fields here applied did not entirely reproduce all the observed structural features.

Efficacy of transurethral botulinum toxin A injections for bladder outlet obstruction: A systematic review and meta-analysis.

INTRODUCTION: Botulinum toxin A (BoNT-A) injections in the prostate gland have been used as a minimally invasive option for treating bladder outlet obstruction (BOO). However, the efficacy of transurethral BoNT-A injections for BOO is not well established in the literature. The aim of this study is to collect evidence on the efficacy of transurethral BoNT-A injections for the treatment of BOO. MATERIALS AND METHODS: This systematic review and meta-analyses was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. A systematic literature search was performed till December 2022. The study population consisted of adult patients diagnosed with BOO, who underwent transurethral injections of BoNT-A for the treatment of BOO. EVIDENCE SYNTHESIS: Out of 883 records, we identified seven studies enrolling 232 participants, of which only one nonrandomized controlled trial was found. Four prospective studies and two retrospective studies. Three studies included patients with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH) and were included in the meta-analysis. Three studies included patients with urethral sphincter hyperactivity. One study included patients with primary bladder neck disease (PBND). All studies showed significant improvements from baseline in maximum urinary flow rate (Qmax), International Prostate Symptom Score (IPSS), and postvoid residual (PVR) at 3 and 6 months. The adverse events were mild in all studies. Hematuria, UTI, and urinary retention were reported across all studies. CONCLUSION: In conclusion, transurethral BoNT-A injections have been shown to improve LUTS, QoL, and urodynamic parameters of individuals with BOO at 3 and 6 months after injections, and no serious adverse effects have been reported. However, data on the long-term benefits of this treatment are scarce, and more prospective, randomized studies with larger samples examining various injection techniques, dosages, and extended follow-up of recurrent injections are needed.

Etiology, presentation and management of urinary tract infections in multiple sclerosis patients: A review of the current literature.

Urinary tract infections (UTIs) present a formidable challenge in the care of individuals affected by multiple sclerosis (MS). Lower urinary tract dysfunction is a prevalent issue among MS patients, predisposing them to an elevated risk of UTIs. When left untreated, UTIs can further exacerbate the already compromised quality of life in individuals with MS. The diagnosis and management of UTIs in MS patients necessitate a careful clinical evaluation. The objective of this review is to delineate preventive strategies and current and developing therapeutic approaches for preventing and treating UTIs associated with urinary dysfunction, catheterization, and upper urinary tract infections in patients with MS. Effectively addressing UTIs and urinary tract dysfunction in individuals with multiple sclerosis calls for a comprehensive, interdisciplinary approach.

Robot-Assisted Radical Prostatectomy Performed with the Novel Hugo™ RAS System: A Systematic Review and Pooled Analysis of Surgical, Oncological, and Functional Outcomes.

Background/Objectives: to assess surgical, oncological, and functional outcomes of robot-assisted radical prostatectomy (RARP) performed using the novel Hugo™ RAS system. Methods: A systematic review was conducted following the PRISMA guidelines, using PubMed, Web of Science, Scopus, and Embase databases. Eligible papers included studies involving adult males undergoing RARP with the Hugo™ RAS platform, with at least ten patients analyzed. The pooled analysis was performed using a random-effect model. Results: Quantitative analysis was conducted on 12 studies including 579 patients. The pooled median docking time, console time, and operative time were 11 min (95% CI 7.95-14.50; I2 = 98.4%, ten studies), 142 min (95% CI 119.74-164.68; I2 = 96.5%, seven studies), and 176 min (95% CI 148.33-203.76; I2 = 96.3%, seven studies), respectively. The pooled median estimated blood loss was 223 mL (95% CI 166.75-280.17; I2 = 96.5%, eleven studies). The pooled median length of hospital stay and time to catheter removal were 2.8 days (95% CI 1.67-3.89; I2 = 100%, ten studies) and 8.3 days (95% CI 5.53-11.09; I2 = 100%, eight studies), respectively. The pooled rate of postoperative CD ≥ 2 complications was 4.1% (95% CI 1-8.5; I2 = 63.6%, eleven studies). The pooled rate of positive surgical margins and undetectable postoperative PSA were 20% (95% CI 12.6-28.5; I2 = 71.5%, nine studies) and 94.2% (95% CI 87.7-98.6; I2 = 48.9%, three studies), respectively. At three months, a pooled rate of social continence of 81.9% (95% CI 73.8-88.9; I2 = 66.7%, seven studies) was found. Erectile function at six months was 31% in one study. Conclusions: despite the preliminary nature of the evidence, this systematic review and pooled analysis underscores the feasibility, safety, and reproducibility of the Hugo™ RAS system in the context of RARP.

Robot-Assisted Radical Prostatectomy Performed with the Novel Surgical Robotic Platform Hugo™ RAS: Monocentric First Series of 132 Cases Reporting Surgical, and Early Functional and Oncological Outcomes at a Tertiary Referral Robotic Center.

BACKGROUND: Robotic-assisted surgery is the gold standard for performing radical prostatectomy (RARP), with new robotic devices such as HugoTM RAS gaining prominence worldwide. OBJECTIVE: We report the surgical, perioperative, and early postoperative outcomes of RARP using HugoTM RAS. DESIGN, SETTING, AND PARTICIPANTS: Between April 2022 and October 2023, we performed 132 procedures using the Montsouris technique with a four-robotic-arm configuration in patients with biopsy-proven prostate cancer (PCa). OUTCOME MEASURES: We collected intraoperative and perioperative data during hospitalization, along with follow-up data at predefined postoperative intervals of 3 and 6 months. RESULTS AND LIMITATIONS: Lymphadenectomy was performed in 25 procedures, with a bilateral nerve-sparing technique in 33 and a monolateral nerve-sparing technique in 33 cases. The mean total surgery time was 242 (±57) min, the mean console time was 124 (±48) min, and the mean docking time was 10 (±2) min. We identified 17 system errors related to robotic arm failures, 9 robotic instrument breakdowns, and 8 significant conflicts between robotic arms. One post-operative complication was classified as Clavien-Dindo 3b. None of the adverse events, whether singular or combined, increased the operative time. Positive margins (pR1) were found in 54 (40.9%) histological specimens, 37 (28.0%) of which were clinically significant. At 3 and 6 months post-surgery, the PSA levels were undetectable in 94.6% and 92.1% of patients, respectively. Social urinary continence was regained in 86% after 6 months. Limitations of our study include its observational monocentric case-series design and the short follow-up data for functional and oncological outcomes. CONCLUSIONS: Our initial experience highlights the reliability of the HugoTM RAS system in performing RARP. Additionally, we also list problems and solutions found in our daily work.