The Stability of Hydrogen-Bonded Ion-Pair Complex Unexpectedly Increases with Increasing Solvent Polarity.

The generally observed decrease of the electrostatic energy in the complex with increasing solvent polarity has led to the assumption that the stability of the complexes with ion-pair hydrogen bonds decreases with increasing solvent polarity. Besides, the smaller solvent-accessible surface area (SASA) of the complex in comparison with the isolated subsystems results in a smaller solvation energy of the latter, leading to a destabilization of the complex in the solvent compared to the gas phase. In our study, which combines Nuclear Magnetic Resonance, Infrared Spectroscopy experiments, quantum chemical calculations, and molecular dynamics (MD) simulations, we question the general validity of this statement. We demonstrate that the binding free energy of the ion-pair hydrogen-bonded complex between 2-fluoropropionic acid and n-butylamine (CH3CHFCOO-…NH3But+) increases with increased solvent polarity. This phenomenon is rationalized by a substantial charge transfer between the subsystems that constitute the ion-pair hydrogen-bonded complex. This unexpected finding introduces a new perspective to our understanding of solvation dynamics, emphasizing the interplay between solvent polarity and molecular stability within hydrogen-bonded systems.

Impact of dielectric constant of solvent on the formation of transition metal-ammine complexes.

The DFT-level computational investigations into Gibbs free energies (ΔG) demonstrate that as the dielectric constant of the solvent increases, the stabilities of [M(NH3 )n ]2+/3+ (n = 4, 6; M = selected 3d transition metals) complexes decrease. However, there is no observed correlation between the stability of the complex and the solvent donor number. Analysis of the charge transfer and Wiberg bond indices indicates a dative-bond character in all the complexes. The solvent effect assessed through solvation energy is determined by the change in the solvent accessible surface area (SASA) and the change in the charge distribution that occurs during complex formation. It has been observed that the SASA and charge transfer are different in the different coordination numbers, resulting in a variation in the solvent effect on complex stability in different solvents. This ultimately leads to a change between the relative stability of complexes with different coordination numbers while increasing the solvent polarity for a few complexes. Moreover, the findings indicate a direct relationship between ΔΔG (∆Gsolvent -∆Ggas ) and ΔEsolv , which enables the computation of ΔG for the compounds in a particular solvent using only ΔGgas and ΔEsolv . This approach is less computationally expensive.

Trends in the stability of covalent dative bonds with variable solvent polarity depend on the charge transfer in the Lewis electron-pair system.

In general, the stability of neutral complexes with dative bonds increases as the polarity of the solvent increases. This is based on the fact that the dipole moment of the complex increases as the charge transferred from the donor to the acceptor increases. As a result, the solvation energy of the complex becomes greater than that of subsystems, causing an increase in the stabilization energy with increasing solvent polarity. Our research confirms this assumption, but only when the charge transfer is sufficiently large. If it is below a certain threshold, the increase in the complex's dipole moment is insufficient to result in a higher solvation energy than subsystems. Thus, the magnitude of the charge transfer in the Lewis electron-pair system determines the stability trends of dative bonds with varying solvent polarity. We used molecular dynamics (MD) simulations based on an explicit solvent model, which is considered more reliable, to verify the results obtained with a continuous solvent model.

Targeting the insulin receptor with hormone and peptide dimers.

Insulin is a key hormone involved in the regulation of overall energetic homeostasis of the organism. The dimeric character of the receptor for insulin evokes ideas about its activation or inhibition with peptide dimers that could either trigger or block the structural transition of the insulin receptor, leading to its activation. Herewith, we present the chemical engineering and biological characterization of several series of insulin dimers or dimers of specific peptides that should be able to bind receptors for insulin or insulin growth factor 1. The hormones or peptides in the dimers were interconnected with different linkers, consisting of triazole moieties and 3, 6, 8, 11, or 23 polyethylene glycol units. The prepared dimers were weaker in binding to insulin receptors than human insulin. However, some of the insulin dimers showed preferential binding specificity toward the isoform A of the insulin receptor, and the insulin dimers also stimulated the insulin receptor more strongly than would be consistent with their binding affinities. Our results suggest that designing insulin dimers may be a promising strategy for modulating the ability of the hormone to activate the receptor or to alter its specificity toward insulin receptor isoforms.

Unexpected Strengthening of the H-Bond Complexes in a Polar Solvent Due to a More Efficient Solvation of the Complex Compared to Isolated Monomers.

It is generally assumed that hydrogen-bonded complexes are less stable in solvents than in the gas phase and that their stability decreases with increasing solvent polarity. This assumption is based on the size of the area available to the solvent, which is always smaller in the complex compared to the subsystems, thereby reducing the solvation energy. This reduction prevails over the amplification of the electrostatic hydrogen bond by the polar solvent. In this work, we show, using experimental IR spectroscopy and DFT calculations, that there are hydrogen-bonded complexes whose stability becomes greater with increasing solvent polarity. The explanation for this surprising stabilization is based on the analysis of the charge redistribution in the complex leading to increase of its dipole moment and solvation energy. Constrained DFT calculations have shown a dominant role of charge transfer over polarization effects for dipole moment and solvation energy.

The stability of covalent dative bond significantly increases with increasing solvent polarity.

It is generally expected that a solvent has only marginal effect on the stability of a covalent bond. In this work, we present a combined computational and experimental study showing a surprising stabilization of the covalent/dative bond in Me3NBH3 complex with increasing solvent polarity. The results show that for a given complex, its stability correlates with the strength of the bond. Notably, the trends in calculated changes of binding (free) energies, observed with increasing solvent polarity, match the differences in the solvation energies (ΔEsolv) of the complex and isolated fragments. Furthermore, the studies performed on the set of the dative complexes, with different atoms involved in the bond, show a linear correlation between the changes of binding free energies and ΔEsolv. The observed data indicate that the ionic part of the combined ionic-covalent character of the bond is responsible for the stabilizing effects of solvents.

SQM/COSMO Scoring Function: Reliable Quantum-Mechanical Tool for Sampling and Ranking in Structure-Based Drug Design.

Invited for this month's cover is the group of Prof. Pavel Hobza, Czech Academy of Sciences, Prague. The cover picture shows a powerful automated quantum mechanics based SQM/COSMO approach to protein-ligand scoring. It comprises thorough preparation of ligand structures, extensive generation of binding complexes, fast geometry relaxation and reliable affinity prediction. Read the full text of the Minireview at 10.1002/cplu.202000120.

Chelating Polymers for Hereditary Hemochromatosis Treatment.

Hemochromatosis (iron overload) encompasses a group of diseases that are characterized by a toxic hyperaccumulation of iron in parenchymal organs. Currently, only few treatments for this disease have been approved; however, all these treatments possess severe side effects. In this study, a paradigm for hemochromatosis maintenance/preventive therapy is investigated: polymers with negligible systemic biological availability form stable complexes with iron ions in the gastrointestinal tract, which reduces the biological availability of iron. Macroporous polymer beads are synthesized with three different iron-chelating moieties (benzene-1,2-diol, benzene-1,2,3-triol, and 1,10-phenanthroline). The polymers rapidly chelate iron ions from aqueous solutions in vitro in the course of minutes, and are noncytotoxic and nonprooxidant. Moreover, the in vivo biodistribution and pharmacokinetics show a negligible uptake from the gastrointestinal tract (using 125 I-labeled polymer and single photon emission computed tomography/computed tomography), which generally prevents them from having systemic side effects. The therapeutic efficacy of the prepared polymers is successfully tested in vivo, and exhibits a significant inhibition of iron uptake from the gastrointestinal tract without any noticeable signs of toxicity. Furthermore, an in silico method is developed for the prediction of chelator selectivity. Therefore, this paradigm can be applied to the next-generation maintenance/preventive treatment for hemochromatosis and/or other diseases of similar pathophysiology.

SQM/COSMO Scoring Function: Reliable Quantum-Mechanical Tool for Sampling and Ranking in Structure-Based Drug Design.

Quantum mechanical (QM) methods have been gaining importance in structure-based drug design where a reliable description of protein-ligand interactions is of utmost significance. However, strategies i. e. QM/MM, fragmentation or semiempirical (SQM) methods had to be pursued to overcome the unfavorable scaling of QM methods. Various SQM-based approaches have significantly contributed to the accuracy of docking and improvement of lead compounds. Parametrizations of SQM and implicit solvent methods in our laboratory have been instrumental to obtain a reliable SQM-based scoring function. The experience gained in its application for activity ranking of ligands binding to tens of protein targets resulted in setting up a faster SQM/COSMO scoring approach, which outperforms standard scoring methods in native pose identification for two dozen protein targets with ten thousand poses. Recently, SQM/COSMO was effectively applied in a proof-of-concept study of enrichment in virtual screening. Due to its superior performance, feasibility and chemical generality, we propose the SQM/COSMO approach as an efficient tool in structure-based drug design.

Description of non-covalent interactions in SCC-DFTB methods.

We have analyzed the description of non-covalent interactions in multiple variants of the self-consistent charges density functional tight binding (SCC-DFTB) method. While the description of London dispersion can be easily improved by empirical correction, hydrogen bonding poses a much more difficult problem. We have implemented an interaction energy decomposition scheme that allowed us to quantify the error at the level of first-order electrostatic and polarization terms. Both are underestimated because of the monopole approximation used in SCC-DFTB, with the latter being affected also by the use of minimal basis set. Among the methods tested, SCC-DFTB with the empirical D3H4 corrections worked best. To make this correction compatible with the latest development in SCC-DFTB, we have reparameterized it for use with third-order SCC-DFTB with the 3OB parameter set. © 2017 Wiley Periodicals, Inc.

Precise tuning of cationic cyclophanes toward highly selective fluorogenic recognition of specific biophosphate anions.

Cationic cyclophanes with bridging and spacer groups possess well-organized semirigid cavities and are able to encapsulate and stabilize anionic species through diverse molecular interactions. We highlight the precise tuning of functionalized cyclophanes toward selective recognition of AMP, GTP, and pyrophosphate (PPi) using fluorescence, NMR spectroscopy, and density functional theory (DFT).