The importance of relativistic effects on the NMR parameters in heavy-atom (HA) compounds, partic... more The importance of relativistic effects on the NMR parameters in heavy-atom (HA) compounds, particularly the SO-HALA (Spin−Orbit Heavy Atom on the Light Atom) effect on NMR chemical shifts, has been known for about 40 years. Yet, a general correlation between the electronic structure and SO-HALA effect has been missing. By analyzing 1 H NMR chemical shifts of the sixth-period hydrides (Cs−At), we discovered general electronic-structure principles and mechanisms that dictate the size and sign of the SO-HALA NMR chemical shifts. In brief, partially occupied HA valence shells induce relativistic shielding at the light atom (LA) nuclei, while empty HA valence shells induce relativistic deshielding. In particular, the LA nucleus is relativistically shielded in 5d 2 −5d 8 and 6p 4 HA hydrides and deshielded in 4f 0 , 5d 0 , 6s 0 , and 6p 0 HA hydrides. This general and intuitive concept explains periodic trends in the 1 H NMR chemical shifts along the sixth-period hydrides (Cs−At) studied in this work. We present substantial evidence that the introduced principles have a general validity across the periodic table and can be extended to nonhydride LAs. The decades-old question of why compounds with occupied frontier π molecular orbitals (MOs) cause SO-HALA shielding at the LA nuclei, while the frontier σ MOs cause deshielding is answered. We further derive connection between the SO-HALA NMR chemical shifts and Spin−Orbit-induced Electron Deformation Density (SO-EDD), a property that can be obtained easily from differential electron densities and can be represented graphically. SO-EDD provides an intuitive understanding of the SO-HALA effect in terms of the depletion/ concentration of the electron density at LA nuclei caused by spin−orbit coupling due to HA in the presence of a magnetic field. Using an analogy between the SO-EDD concept and arguments from classic NMR theory, the complex question of the SO-HALA NMR chemical shifts becomes easily understandable for a wide chemical audience.
A recent study (Sci. Adv. 2017, 3, e1602833) has shown that FH···OH 2 hydrogen bond in a HF·H 2 O... more A recent study (Sci. Adv. 2017, 3, e1602833) has shown that FH···OH 2 hydrogen bond in a HF·H 2 O pair substantially shortens, and the HÀF bond elongates upon en-capsulation of the cluster in C 70 fullerene. This has been attributed to compression of the HF·H 2 O pair inside the cavity of C 70. Herein, we present theoretical evidence that the effect is not caused by a mere compression of the H 2 O·HF pair, but it is related to a strong lone-pair–p (LP–p) bonding with the fullerene cage. To support this argument , a systematic electronic structure study of selected small molecules (HF, H 2 O, and NH 3) and their pairs enclosed in fullerene cages (C 60 , C 70 , and C 90) has been performed. Bonding analysis revealed unique LP–p cage interactions with a charge-depletion character in the bonding region, unlike usual LP–p bonds. The LP–p cage interactions were found to be responsible for elongation of the HÀF bond. Thus, the HF appears to be more acidic inside the cage. The shortening of the FH···OH 2 contact in (HF·H 2 O)@C 70 originates from an increased acidity of the HF inside the fullerenes. Such trends were also observed in other studied systems.
The potential of paramagnetic ruthenium(III) compounds for use as anticancer metallodrugs has bee... more The potential of paramagnetic ruthenium(III) compounds for use as anticancer metallodrugs has been investigated extensively during the past several decades. However, the means by which these ruthenium compounds are transported and distributed in living bodies remain relatively unexplored. In this work, we prepared several novel ruthenium(III) compounds with the general structure Na+[trans-RuIIICl4(DMSO)(L)]− (DMSO = dimethyl sulf-oxide), where L stands for pyridine or imidazole linked with adamantane, a hydrophobic chemophore. The supramolecular interactions of these compounds with macrocyclic carriers of the cyclodextrin (CD) and cucurbit[n]uril (CB) families were investigated by NMR spectroscopy, X-ray diffraction analysis, isothermal titration calorimetry, and relativistic DFT methods. The long-range hyperfine NMR effects of the paramagnetic guest on the host macrocycle are related to the distance between them and their relative orientation in the host−guest complex. The CD and CB macrocyclic carriers being studied in this account can be attached to a vector that attracts the drug-carrier system to a specific biological target and our investigation thus introduces a new possibility in the field of targeted delivery of anticancer metallodrugs based on ruthenium(III) compounds.
NMR spectroscopy is an indispensable tool in characterizing molecular systems, including transiti... more NMR spectroscopy is an indispensable tool in characterizing molecular systems, including transition-metal complexes. However, paramagnetic transition-metal complexes such as those with ruthenium in the +3 oxidation state are troublemakers because their unpaired electrons induce a fast nuclear spin relaxation that significantly broadens their NMR resonances. We recently demonstrated that the electronic and spin structures of paramagnetic Ru(III) systems can be characterized in unprecedented details by combining experimental NMR results with relativistic density-functional theory (Novotny et al. J. Am. Chem. Soc. 2016, 138, 8432). In this study we focus on paramagnetic analogs of NAMI with the general structure [3-R-pyH]+ trans-[Ru(III)Cl4(DMSO)(3-R-py)]− , where 3-R-py stands for a 3-substituted pyridine. The experimental NMR data are interpreted in terms of the contributions of hyperfine (HF) NMR shielding and the distribution of spin density calculated using relativistic DFT. The DFT computational methodology is evaluated, and the effects of substituents, environment, and relativity on the hyperfine shielding are discussed. Particular attention is paid to the analysis of the fundamental Fermi-contact (FC), spin-dipole (SD), and paramagnetic spin−orbit (PSO) terms that contribute to the hyperfine 1 H and 13 C NMR shifts of the individual atoms in the pyridine ligands and the spin-polarization effects in the ligand system that are linked to the character of the metal−ligand bond. The individual HF shielding terms are systematically discussed as they relate to the traditional, but somewhat mixed, contact and pseudocontact NMR contributions used extensively by experimental spectroscopists in biomolecular NMR and the development of PARACEST magnetic-resonance contrast agents.
Relativistic effects significantly affect various spectro-scopic properties of compounds containi... more Relativistic effects significantly affect various spectro-scopic properties of compounds containing heavy elements. Particularly in Nuclear Magnetic Resonance (NMR) spectroscopy, the heavy atoms strongly influence the NMR shielding constants of neighboring light atoms. In this account we analyze paramagnetic contributions to NMR shielding constants and their modulation by relativistic spin−orbit effects in a series of transition-metal complexes of Pt(II), Au(I), Au(III), and Hg(II). We show how the paramagnetic NMR shielding and spin− orbit effects relate to the character of the metal−ligand (M−L) bond. A correlation between the (back)-donation character of the M−L bond in d 10 Au(I) complexes and the propagation of the spin−orbit (SO) effects from M to L through the M−L bond influencing the ligand NMR shielding via the Fermi-contact mechanism is found and rationalized by using third-order perturbation theory. The SO effects on the ligand NMR shielding are demonstrated to be driven by both the electronic structure of M and the nature of the trans ligand, sharing the σ-bonding metal orbital with the NMR spectator atom L. The deshielding paramagnetic contribution is linked to the σ-type M−L bonding orbitals, which are notably affected by the trans ligand. The SO deshielding role of σ-type orbitals is enhanced in d 10 Hg(II) complexes with the Hg 6p atomic orbital involved in the M−L bonding. In contrast, in d 8 Pt(II) complexes, occupied π-type orbitals play a dominant role in the SO-altered magnetic couplings due to the accessibility of vacant antibonding σ-type MOs in formally open 5d-shell (d 8). This results in a significant SO shielding at the light atom. The energy-and composition-modulation of σ-vs π-type orbitals by spin−orbit coupling is rationalized and supported by visualizing the SO-induced changes in the electron density around the metal and light atoms (spin−orbit electron deformation density, SO-EDD).
State–of–the–art computations combined with Ziegler–Rauk energy decomposition analysis are employ... more State–of–the–art computations combined with Ziegler–Rauk energy decomposition analysis are employed to introduce a new class of anti–electrostatic ion–σ bonds with considerable stability and substantial contribution from charge–transfer and dispersion between ions and finite–size functionalized graphane flakes, G–XY. G–XYs have diverse electric multipolar moments that are comparable with those of newly synthesized all–cis–hexa–halocyclohexanes. The strong long–range electrostatic and Pauli repulsions between some G–XYs and certain ions induce a gas–phase energy barrier to physisorption of ions on the surface of G–XYs. Yet, the repulsive interactions can be overbalanced by the strong orbital interactions operating in the formation of ion–σ complexes at short–range, leading to covalent–type intermolecular bonds as strong as –34 kcal.mol–1.
Supramolecular interactions were generally classified as non-covalent. However, recent studies ha... more Supramolecular interactions were generally classified as non-covalent. However, recent studies have demonstrated that many of these formally non-covalent interactions are stabilized by a significant covalent component. Herein we show for systems of the general structure [MX6]2-:YX2 (M = Se or Pt; Y = S, Se, or Te; X = F, Cl, Br, I) featuring bifurcated chalcogen bonding that, while the electrostatic parameters are useful for estimating the long-range electrostatic component of the interaction, they fail to predict the correct order of the binding energies in a series of compounds. Instead, the Lewis basicity of the individual substituents X on the chalcogen atom governs the trends in the binding energies via fine-tuning the covalent character of the chalcogen bond. The effects of substituents on the binding energy and the supramolecular electron sharing are consistently identified by an arsenal of theoretical methods ranging from approaches based on the quantum chemical topology to analytical tools based on the localized molecular orbitals. The chalcogen bonding investigated in this work is driven by orbital interactions with significant electron sharing, which can be designated as supramolecular covalence.
The topology and energetics of guanine (G) quadruplexes is governed by supramolecular interaction... more The topology and energetics of guanine (G) quadruplexes is governed by supramolecular interactions within their strands. In this work, an extensive quantum mechanical (QM) study has been performed to analyze supramolecular interactions that shape the stems of (4+0) parallel (P) and (2+2) antiparallel (AP) quadruplex systems. The large-scale (≈400 atoms) models of P and AP were constructed from high-quality experimental structures. The results provide evidence that each of the P and AP structures is shaped by a distinct network of supramolecular interactions. Analysis of electron topological characteristics of hydrogen bonds in P and AP systems indicates that the P model benefits from stronger intratetrad hydrogen bonding. For intertetrad stacking interactions, both noncovalent interaction plot and energy decomposition analysis approaches suggest that the stem of the P quadruplex benefits more from stacking than that of the AP stem; the difference in energetic stabilization for the two topologies is about 10 %. Stronger hydrogen-bonding and stacking interactions in the stem of the P quadruplex, relative to those in the AP system, can be an important indicator to explain the experimental observations that guanine-rich oligonucleotides tend to form all-parallel stems with an all-anti orientation of nucleobases. However, in addition to intrinsic stabilization, partial desolvation effects, which affect the energetics and dynamics of the G-quadruplex folding process, call for further investigations.
Anion–π interactions have been shown to stabilize flavoproteins and to regulate the redox potenti... more Anion–π interactions have been shown to stabilize flavoproteins and to regulate the redox potential of the flavin cofactor. They are commonly attributed to electrostatic forces. Herein we show that anion–flavin interactions can have a substantial charge-transfer component. Our conclusion emanates from a multi-approach theoretical analysis and is backed by previously reported observations of absorption bands, originating from charge transfer between oxidized flavin and proximate cysteine thiolate groups. This partial covalency of anion–flavin contacts renders classical simulations of flavoproteins questionable.
In this work we investigated the influence of an external electric field on the arrangement of th... more In this work we investigated the influence of an external electric field on the arrangement of the solvent shells around ions interacting with a carbon-based receptor. Our survey reveals that the mechanism of interaction between a monoatomic ion and a π-type ion receptor varies by the variation in the solvent polarity, the nature of the ion, and the strength of the external field. The characteristics of the ion–surface interaction in nonpolar solvents are similar to those observed in a vacuum. However, in water, we identified two mechanisms. Soft and polarizable ions preferentially interact with the π-receptor. In contrast, two bonded states were found for hard ions. A fully solvated ion, weakly interacting with the receptor at weak field, and a strong π-complex at the strong-field regime were identified. An abrupt variation in the potential energy surface (PES) associated with the rearrangement of the solvation shell on the surface of the receptor induced by an external field was observed both in implicit and explicit solvent environments. The electric field at which the solvation shell breaks is proportional to the hardness of the ion as has been suggested recently based on experimental observations.
The role of relativistic effects on 1H NMR chemical shifts of Sn(II) and Pb(II) hydrides is inves... more The role of relativistic effects on 1H NMR chemical shifts of Sn(II) and Pb(II) hydrides is investigated by using fully relativistic DFT calculations. The stability of possible Pb(II) hydride isomers is studied together with their 1H NMR chemical shifts, which are predicted in the high-frequency region, up to 90 ppm. These 1H signals are dictated by sizable relativistic contributions due to spin-orbit coupling at the heavy atom and can be as large as 80 ppm for a hydrogen atom bound to Pb(II). Such high-frequency 1H NMR chemical shifts of Pb(II) hydride resonances cannot be detected in the 1H NMR spectra with standard experimental setup. Extended 1H NMR spectral ranges are thus suggested for studies of Pb(II) compounds. Modulation of spin-orbit relativistic contribution to 1H NMR chemical shift is found to be important also in the experimentally known Sn(II) hydrides. Because the 1H NMR chemical shifts were found to be rather sensitive to the changes in the coordination sphere of the central metal in both Sn(II) and Pb(II) hydrides, their application for structural investigation is suggested.
Imidazolium-based guests containing two distinct binding epitopes are capable of binding beta-cyc... more Imidazolium-based guests containing two distinct binding epitopes are capable of binding beta-cyclodextrin and cucurbit[6/7]uril (CB) simultaneously to form hetero-ternary 1:1:1 inclusion complexes. In the final configuration, the hosts occupy binding sites disfavored in the binary complexes because of the chemically induced reorganization of the intermediate 1:1 aggregate. In addition, the reported guests are capable of binding two CBs to form either 1:2 or 1:1:1 ternary assemblies despite consisting of a single cationic moiety. Whereas the adamantane site binds CB solely via hydrophobic interactions, the CB unit at the butyl site is stabilized by a combination of hydrophobic and ion-dipole interactions.
Lone-pair–π (lp–π) interactions have been suggested to stabilize DNA and protein structures, and ... more Lone-pair–π (lp–π) interactions have been suggested to stabilize DNA and protein structures, and to participate in the formation of DNA–protein complexes. To elucidate their physical origin, we have carried out a theoretical multi-approach analysis of two biologically relevant model systems, water–indole and water–uracil complexes, which we compared with the structurally similar chloride-tetracyanobenzene (TCB) complex previously shown to contain a strong charge-transfer (CT) binding component. We demonstrate that the CT component in lp–π interactions between water and indole/uracil is significantly smaller than that stabilizing the Cl-–TCB reference system. The strong lp(Cl-)–π(TCB) orbital interaction is characterized by a small energy gap and an efficient lp–π* overlap. In contrast, in lp–π interactions between water and indole or uracil, the corresponding energy gap is larger and the overlap less efficient. As a result, water–uracil and water–indole interactions are weak forces composed by smaller contributions from all energy components: electrostatics, polarization, dispersion, and charge transfer. In addition, indole exhibits a negative electrostatic potential at its π-face, making lp–π interactions less favorable than O–H...π hydrogen bonding. Consequently, some of the water–tryptophan contacts observed in X-ray structures of proteins and previously interpreted as lp–π interactions [Luisi, et al., Proteins, 2004, 57, 1–8], might in fact arise from O–H...π hydrogen bonding.
Repetitive guanine-rich nucleic acid sequences play a crucial role in maintaining genome stabilit... more Repetitive guanine-rich nucleic acid sequences play a crucial role in maintaining genome stability and the cell life cycle and represent potential targets for regulatory drugs. Recently, it has been demonstrated that guanine-based ligands with a porphyrin core can be used as markers of G-quadruplex assemblies in cell tissues. Herein, model systems of guanine-based ligands are explored by DFT methods. The energies of formation of modified guanine tetrads and those of modified tetrads stacked on the top of natural guanine tetrads have been calculated. The interaction energy has been decomposed into contributions from hydrogen bonding, stacking, and ion coordination and a twist–rise potential energy scan has been performed to find the individual local minima. Energy decomposition analysis reveals the impact of various substituents (F, Cl, Br, I, Me, NMe2) on individual energy terms. In addition, cooperative reinforcement in forming the modified and stacked tetrads, as well as the frontier orbitals participating in the hydrogen-bonding framework involving the HOMO–LUMO gap between the occupied s HOMO on the proton-accepting C=O and =N- groups and unoccupied s LUMO on the N-H groups, has been studied. The investigated systems are demonstrated to have a potential in ligand development, mainly due to stacking enhancement compared with natural guanine, which is used as a reference.
Ruthenium-based compounds are potential candidates for use as anticancer metallodrugs. The centra... more Ruthenium-based compounds are potential candidates for use as anticancer metallodrugs. The central ruthenium atom can be in the oxidation state +2 (e.g., RAPTA, RAED) or +3 (e.g., NAMI, KP). In this study we focus on paramagnetic NAMI analogs of a general structure [4-R-pyH] + trans-[Ru III Cl 4 (DMSO)(4-R-py)] − , where 4-R-py stands for a 4-substituted pyridine. As paramagnetic systems are generally considered difficult to characterize in detail by NMR spectroscopy, we performed a systematic structural and methodological NMR study of complexes containing variously substituted pyridines. The effect of the paramagnetic nature of these complexes on the 1 H and 13 C NMR chemical shifts was systematically investigated by temperature-dependent NMR experiments and density-functional theory (DFT) calculations. To understand the electronic factors influencing the orbital (δ orb , temperature-independent) and paramagnetic (δ para , temperature-dependent) contributions to the total NMR chemical shifts, a relativistic two-component DFT approach was used. The paramagnetic contributions to the 13 C NMR chemical shifts are correlated with the distribution of spin density in the ligand moiety and the 13 C isotropic hyperfine coupling constants, A iso (13 C), for the individual carbon atoms. To analyze the mechanism of spin distribution in the ligand, the contributions of molecular spin−orbitals (MSOs) to the hyperfine coupling constants and the spatial distribution of the z-component of the spin density in the MSOs calculated at the relativistic four-component DFT level are discussed and rationalized. The significant effects of the substituent and the solvent on δ para , particularly the contact contribution, are demonstrated. This work should contribute to further understanding of the link between the electronic structure and the NMR chemical shifts in open-shell systems, including the ruthenium-based metallodrugs investigated in this account.
Substituted coronenes, a family of ion-π receptors whose ion-affinities can be explained exclusiv... more Substituted coronenes, a family of ion-π receptors whose ion-affinities can be explained exclusively neither via ion-quadrupole nor induction/polarization mechanisms, are studied. The best descriptors of ion-affinity among these species are those characterizing charge-transfer between ions and the π-systems, e.g. vertical ionization potential, electron affinity, and the relative energies of charge-transfer excited-states (CTESs). The variation of the electric multipole moments, polarizability, binding energy, and relative energy of CTESs in the presence of an external electric field (EEF) is evaluated. The results indicate that the EEF has a negligible effect on the polarizability and quadrupole moment of the systems. However, it significantly affects the binding energies, CTES energies, and the dipole moments of the receptors. Contrary to the changes in the dipole moment, the variation pattern of the binding energy is more consistent with the pattern observed for the CTES energy changes. Finally, by analyzing the exchange-correlation component of the binding energy we demonstrate that the increased binding energy, i.e. bond strengthening, originates from enhanced electron sharing and multi-center covalency between the ions and the π-systems as a result of the state-mixing between the ground-state and the CTESs. According to our findings, we hypothesize that the electron sharing and in extreme cases the multi-center covalency are the main driving forces for complexation of ions with extended π-receptors such as carbon nano-structures.
On the basis of four-component relativistic DFT calculations, large relativistic spin−orbit effec... more On the basis of four-component relativistic DFT calculations, large relativistic spin−orbit effects amounting to more than 200 ppm for 13C and more than 1000 ppm for 29Si are identified to be the main contributions to high-frequency 13C and 29Si NMR chemical shifts in Tl(I) and Pb(II) compounds. Origin of the large SO deshielding is traced to highly efficient 6p−6p* orbital magnetic couplings.
The influence of various sugar-residue modifications on intrinsic energetic, conformational, and ... more The influence of various sugar-residue modifications on intrinsic energetic, conformational, and mechanical properties of 2´-deoxyribonucleotide-5´-monophosphates (dNs) was comprehensively investigated using modern quantum chemical approaches. In total, fourteen sugar modifications, including double bonds and heteroatoms (S, N) inside the sugar ring, as well as fluorination in various positions, were analyzed. Among hundreds of possible conformational states of dNs, only two - AI and BI, corresponding to the most biologically significant forms of a double-helical DNA, were considered for each dN. It was established that the most of the studied modifications tend to strongly stabilize either AI or BI conformation of dNs both in the gas phase and in aqueous solution (modeled by implicit solvent models). Therefore, some of these modifications can be used as a tool for reducing structural polymorphism of nucleic acids in solution as well as for designing oligonucleotides with specific structural features. The evaluation of relaxed force constants (RFC) for glycosidic bonds suggests that the majority of the studied modifications of the sugar residue yield increased strengths of glycosidic bonds in dNs, and can therefore be used for designing modified nucleic acids with an increased resistance to abasic lesions. The most significant reinforcement of the glycosidic bond occurs in dNs containing the CF2 group instead of the O4' oxygen and the fluorine atom at the 2'-alpha-position. The calculation of the RFC and vibrational root-mean-square (VRMS) deviations for conformational degrees of freedom revealed a strong dependence between mechanical properties of dNs and their energetic characteristics. In particular, electronic energies of AI and BI conformers of dNs calculated in vacuo are closely connected with the values of relaxed force constants (RFC) for the delta angle: the higher RFC(delta) values correspond to more energetically favorable conformers.
Exploring the nature of anion-π bonding by means of the Quantum Theory of Atoms in Molecules (QTA... more Exploring the nature of anion-π bonding by means of the Quantum Theory of Atoms in Molecules (QTAIM) and an energy decomposition scheme on the basis of Interacting Quantum Atoms (IQA) theory led us to conclude that these non-classical interactions benefit from “multi-center covalency” far more than from the electrostatics. Comparing to a number of closely related covalent anion-σ complexes reveals that the anion-π systems benefit from an extensive degree of electron sharing between the anions and all atoms of the π-rings. Besides, decomposition of the binding energy into classical (electrostatics) and non-classical (exchange-correlation) components demonstrates that in contrast to previous reports, the anion-π complexes are local minima, if and only if the non-classical contribution to binding energy surpasses that of the electrostatics. This suggests that the stable anion-π complexes with the anions atop the π-rings might be prepared with π-systems that benefit more from the exchange-correlation term, such as extended π-systems, but not with strong electrostatic π-receptors. This conclusion is in line with the tendency of strong π-acids to form the σ-complexes with more covalent character instead of the electrostatic π-complexes.
Intrinsic structural features and energetics of nucleotides containing variously fluorinated suga... more Intrinsic structural features and energetics of nucleotides containing variously fluorinated sugars as potential building blocks of DNA duplexes and quadruplexes are explored systematically using the modern methods of density functional theory (DFT) and quantum chemical topology (QCT). Our results suggest that fluorination at the 2′-β or 2′-α,β positions somewhat stabilizes in vacuo the AI relative to the BI conformations. In contrast, substitution of the CF2 group for the O4′ atom (O4′-CF2 modification) leads to a preference of the BI relative to AI DNA-like conformers. All the studied modifications result in a noticeable increase in the stability of the glycosidic bond [estimated by the relaxed force constants (RFC) approach], with particularly encouraging results for the O4′-CF2 derivative. Consequently, the O4′-CF2 modified systems are suggested and explored as promising scaffolds for the development of duplex and quadruplex structures with reduced propensity to form abasic lesions and to undergo DNA damage.
The importance of relativistic effects on the NMR parameters in heavy-atom (HA) compounds, partic... more The importance of relativistic effects on the NMR parameters in heavy-atom (HA) compounds, particularly the SO-HALA (Spin−Orbit Heavy Atom on the Light Atom) effect on NMR chemical shifts, has been known for about 40 years. Yet, a general correlation between the electronic structure and SO-HALA effect has been missing. By analyzing 1 H NMR chemical shifts of the sixth-period hydrides (Cs−At), we discovered general electronic-structure principles and mechanisms that dictate the size and sign of the SO-HALA NMR chemical shifts. In brief, partially occupied HA valence shells induce relativistic shielding at the light atom (LA) nuclei, while empty HA valence shells induce relativistic deshielding. In particular, the LA nucleus is relativistically shielded in 5d 2 −5d 8 and 6p 4 HA hydrides and deshielded in 4f 0 , 5d 0 , 6s 0 , and 6p 0 HA hydrides. This general and intuitive concept explains periodic trends in the 1 H NMR chemical shifts along the sixth-period hydrides (Cs−At) studied in this work. We present substantial evidence that the introduced principles have a general validity across the periodic table and can be extended to nonhydride LAs. The decades-old question of why compounds with occupied frontier π molecular orbitals (MOs) cause SO-HALA shielding at the LA nuclei, while the frontier σ MOs cause deshielding is answered. We further derive connection between the SO-HALA NMR chemical shifts and Spin−Orbit-induced Electron Deformation Density (SO-EDD), a property that can be obtained easily from differential electron densities and can be represented graphically. SO-EDD provides an intuitive understanding of the SO-HALA effect in terms of the depletion/ concentration of the electron density at LA nuclei caused by spin−orbit coupling due to HA in the presence of a magnetic field. Using an analogy between the SO-EDD concept and arguments from classic NMR theory, the complex question of the SO-HALA NMR chemical shifts becomes easily understandable for a wide chemical audience.
A recent study (Sci. Adv. 2017, 3, e1602833) has shown that FH···OH 2 hydrogen bond in a HF·H 2 O... more A recent study (Sci. Adv. 2017, 3, e1602833) has shown that FH···OH 2 hydrogen bond in a HF·H 2 O pair substantially shortens, and the HÀF bond elongates upon en-capsulation of the cluster in C 70 fullerene. This has been attributed to compression of the HF·H 2 O pair inside the cavity of C 70. Herein, we present theoretical evidence that the effect is not caused by a mere compression of the H 2 O·HF pair, but it is related to a strong lone-pair–p (LP–p) bonding with the fullerene cage. To support this argument , a systematic electronic structure study of selected small molecules (HF, H 2 O, and NH 3) and their pairs enclosed in fullerene cages (C 60 , C 70 , and C 90) has been performed. Bonding analysis revealed unique LP–p cage interactions with a charge-depletion character in the bonding region, unlike usual LP–p bonds. The LP–p cage interactions were found to be responsible for elongation of the HÀF bond. Thus, the HF appears to be more acidic inside the cage. The shortening of the FH···OH 2 contact in (HF·H 2 O)@C 70 originates from an increased acidity of the HF inside the fullerenes. Such trends were also observed in other studied systems.
The potential of paramagnetic ruthenium(III) compounds for use as anticancer metallodrugs has bee... more The potential of paramagnetic ruthenium(III) compounds for use as anticancer metallodrugs has been investigated extensively during the past several decades. However, the means by which these ruthenium compounds are transported and distributed in living bodies remain relatively unexplored. In this work, we prepared several novel ruthenium(III) compounds with the general structure Na+[trans-RuIIICl4(DMSO)(L)]− (DMSO = dimethyl sulf-oxide), where L stands for pyridine or imidazole linked with adamantane, a hydrophobic chemophore. The supramolecular interactions of these compounds with macrocyclic carriers of the cyclodextrin (CD) and cucurbit[n]uril (CB) families were investigated by NMR spectroscopy, X-ray diffraction analysis, isothermal titration calorimetry, and relativistic DFT methods. The long-range hyperfine NMR effects of the paramagnetic guest on the host macrocycle are related to the distance between them and their relative orientation in the host−guest complex. The CD and CB macrocyclic carriers being studied in this account can be attached to a vector that attracts the drug-carrier system to a specific biological target and our investigation thus introduces a new possibility in the field of targeted delivery of anticancer metallodrugs based on ruthenium(III) compounds.
NMR spectroscopy is an indispensable tool in characterizing molecular systems, including transiti... more NMR spectroscopy is an indispensable tool in characterizing molecular systems, including transition-metal complexes. However, paramagnetic transition-metal complexes such as those with ruthenium in the +3 oxidation state are troublemakers because their unpaired electrons induce a fast nuclear spin relaxation that significantly broadens their NMR resonances. We recently demonstrated that the electronic and spin structures of paramagnetic Ru(III) systems can be characterized in unprecedented details by combining experimental NMR results with relativistic density-functional theory (Novotny et al. J. Am. Chem. Soc. 2016, 138, 8432). In this study we focus on paramagnetic analogs of NAMI with the general structure [3-R-pyH]+ trans-[Ru(III)Cl4(DMSO)(3-R-py)]− , where 3-R-py stands for a 3-substituted pyridine. The experimental NMR data are interpreted in terms of the contributions of hyperfine (HF) NMR shielding and the distribution of spin density calculated using relativistic DFT. The DFT computational methodology is evaluated, and the effects of substituents, environment, and relativity on the hyperfine shielding are discussed. Particular attention is paid to the analysis of the fundamental Fermi-contact (FC), spin-dipole (SD), and paramagnetic spin−orbit (PSO) terms that contribute to the hyperfine 1 H and 13 C NMR shifts of the individual atoms in the pyridine ligands and the spin-polarization effects in the ligand system that are linked to the character of the metal−ligand bond. The individual HF shielding terms are systematically discussed as they relate to the traditional, but somewhat mixed, contact and pseudocontact NMR contributions used extensively by experimental spectroscopists in biomolecular NMR and the development of PARACEST magnetic-resonance contrast agents.
Relativistic effects significantly affect various spectro-scopic properties of compounds containi... more Relativistic effects significantly affect various spectro-scopic properties of compounds containing heavy elements. Particularly in Nuclear Magnetic Resonance (NMR) spectroscopy, the heavy atoms strongly influence the NMR shielding constants of neighboring light atoms. In this account we analyze paramagnetic contributions to NMR shielding constants and their modulation by relativistic spin−orbit effects in a series of transition-metal complexes of Pt(II), Au(I), Au(III), and Hg(II). We show how the paramagnetic NMR shielding and spin− orbit effects relate to the character of the metal−ligand (M−L) bond. A correlation between the (back)-donation character of the M−L bond in d 10 Au(I) complexes and the propagation of the spin−orbit (SO) effects from M to L through the M−L bond influencing the ligand NMR shielding via the Fermi-contact mechanism is found and rationalized by using third-order perturbation theory. The SO effects on the ligand NMR shielding are demonstrated to be driven by both the electronic structure of M and the nature of the trans ligand, sharing the σ-bonding metal orbital with the NMR spectator atom L. The deshielding paramagnetic contribution is linked to the σ-type M−L bonding orbitals, which are notably affected by the trans ligand. The SO deshielding role of σ-type orbitals is enhanced in d 10 Hg(II) complexes with the Hg 6p atomic orbital involved in the M−L bonding. In contrast, in d 8 Pt(II) complexes, occupied π-type orbitals play a dominant role in the SO-altered magnetic couplings due to the accessibility of vacant antibonding σ-type MOs in formally open 5d-shell (d 8). This results in a significant SO shielding at the light atom. The energy-and composition-modulation of σ-vs π-type orbitals by spin−orbit coupling is rationalized and supported by visualizing the SO-induced changes in the electron density around the metal and light atoms (spin−orbit electron deformation density, SO-EDD).
State–of–the–art computations combined with Ziegler–Rauk energy decomposition analysis are employ... more State–of–the–art computations combined with Ziegler–Rauk energy decomposition analysis are employed to introduce a new class of anti–electrostatic ion–σ bonds with considerable stability and substantial contribution from charge–transfer and dispersion between ions and finite–size functionalized graphane flakes, G–XY. G–XYs have diverse electric multipolar moments that are comparable with those of newly synthesized all–cis–hexa–halocyclohexanes. The strong long–range electrostatic and Pauli repulsions between some G–XYs and certain ions induce a gas–phase energy barrier to physisorption of ions on the surface of G–XYs. Yet, the repulsive interactions can be overbalanced by the strong orbital interactions operating in the formation of ion–σ complexes at short–range, leading to covalent–type intermolecular bonds as strong as –34 kcal.mol–1.
Supramolecular interactions were generally classified as non-covalent. However, recent studies ha... more Supramolecular interactions were generally classified as non-covalent. However, recent studies have demonstrated that many of these formally non-covalent interactions are stabilized by a significant covalent component. Herein we show for systems of the general structure [MX6]2-:YX2 (M = Se or Pt; Y = S, Se, or Te; X = F, Cl, Br, I) featuring bifurcated chalcogen bonding that, while the electrostatic parameters are useful for estimating the long-range electrostatic component of the interaction, they fail to predict the correct order of the binding energies in a series of compounds. Instead, the Lewis basicity of the individual substituents X on the chalcogen atom governs the trends in the binding energies via fine-tuning the covalent character of the chalcogen bond. The effects of substituents on the binding energy and the supramolecular electron sharing are consistently identified by an arsenal of theoretical methods ranging from approaches based on the quantum chemical topology to analytical tools based on the localized molecular orbitals. The chalcogen bonding investigated in this work is driven by orbital interactions with significant electron sharing, which can be designated as supramolecular covalence.
The topology and energetics of guanine (G) quadruplexes is governed by supramolecular interaction... more The topology and energetics of guanine (G) quadruplexes is governed by supramolecular interactions within their strands. In this work, an extensive quantum mechanical (QM) study has been performed to analyze supramolecular interactions that shape the stems of (4+0) parallel (P) and (2+2) antiparallel (AP) quadruplex systems. The large-scale (≈400 atoms) models of P and AP were constructed from high-quality experimental structures. The results provide evidence that each of the P and AP structures is shaped by a distinct network of supramolecular interactions. Analysis of electron topological characteristics of hydrogen bonds in P and AP systems indicates that the P model benefits from stronger intratetrad hydrogen bonding. For intertetrad stacking interactions, both noncovalent interaction plot and energy decomposition analysis approaches suggest that the stem of the P quadruplex benefits more from stacking than that of the AP stem; the difference in energetic stabilization for the two topologies is about 10 %. Stronger hydrogen-bonding and stacking interactions in the stem of the P quadruplex, relative to those in the AP system, can be an important indicator to explain the experimental observations that guanine-rich oligonucleotides tend to form all-parallel stems with an all-anti orientation of nucleobases. However, in addition to intrinsic stabilization, partial desolvation effects, which affect the energetics and dynamics of the G-quadruplex folding process, call for further investigations.
Anion–π interactions have been shown to stabilize flavoproteins and to regulate the redox potenti... more Anion–π interactions have been shown to stabilize flavoproteins and to regulate the redox potential of the flavin cofactor. They are commonly attributed to electrostatic forces. Herein we show that anion–flavin interactions can have a substantial charge-transfer component. Our conclusion emanates from a multi-approach theoretical analysis and is backed by previously reported observations of absorption bands, originating from charge transfer between oxidized flavin and proximate cysteine thiolate groups. This partial covalency of anion–flavin contacts renders classical simulations of flavoproteins questionable.
In this work we investigated the influence of an external electric field on the arrangement of th... more In this work we investigated the influence of an external electric field on the arrangement of the solvent shells around ions interacting with a carbon-based receptor. Our survey reveals that the mechanism of interaction between a monoatomic ion and a π-type ion receptor varies by the variation in the solvent polarity, the nature of the ion, and the strength of the external field. The characteristics of the ion–surface interaction in nonpolar solvents are similar to those observed in a vacuum. However, in water, we identified two mechanisms. Soft and polarizable ions preferentially interact with the π-receptor. In contrast, two bonded states were found for hard ions. A fully solvated ion, weakly interacting with the receptor at weak field, and a strong π-complex at the strong-field regime were identified. An abrupt variation in the potential energy surface (PES) associated with the rearrangement of the solvation shell on the surface of the receptor induced by an external field was observed both in implicit and explicit solvent environments. The electric field at which the solvation shell breaks is proportional to the hardness of the ion as has been suggested recently based on experimental observations.
The role of relativistic effects on 1H NMR chemical shifts of Sn(II) and Pb(II) hydrides is inves... more The role of relativistic effects on 1H NMR chemical shifts of Sn(II) and Pb(II) hydrides is investigated by using fully relativistic DFT calculations. The stability of possible Pb(II) hydride isomers is studied together with their 1H NMR chemical shifts, which are predicted in the high-frequency region, up to 90 ppm. These 1H signals are dictated by sizable relativistic contributions due to spin-orbit coupling at the heavy atom and can be as large as 80 ppm for a hydrogen atom bound to Pb(II). Such high-frequency 1H NMR chemical shifts of Pb(II) hydride resonances cannot be detected in the 1H NMR spectra with standard experimental setup. Extended 1H NMR spectral ranges are thus suggested for studies of Pb(II) compounds. Modulation of spin-orbit relativistic contribution to 1H NMR chemical shift is found to be important also in the experimentally known Sn(II) hydrides. Because the 1H NMR chemical shifts were found to be rather sensitive to the changes in the coordination sphere of the central metal in both Sn(II) and Pb(II) hydrides, their application for structural investigation is suggested.
Imidazolium-based guests containing two distinct binding epitopes are capable of binding beta-cyc... more Imidazolium-based guests containing two distinct binding epitopes are capable of binding beta-cyclodextrin and cucurbit[6/7]uril (CB) simultaneously to form hetero-ternary 1:1:1 inclusion complexes. In the final configuration, the hosts occupy binding sites disfavored in the binary complexes because of the chemically induced reorganization of the intermediate 1:1 aggregate. In addition, the reported guests are capable of binding two CBs to form either 1:2 or 1:1:1 ternary assemblies despite consisting of a single cationic moiety. Whereas the adamantane site binds CB solely via hydrophobic interactions, the CB unit at the butyl site is stabilized by a combination of hydrophobic and ion-dipole interactions.
Lone-pair–π (lp–π) interactions have been suggested to stabilize DNA and protein structures, and ... more Lone-pair–π (lp–π) interactions have been suggested to stabilize DNA and protein structures, and to participate in the formation of DNA–protein complexes. To elucidate their physical origin, we have carried out a theoretical multi-approach analysis of two biologically relevant model systems, water–indole and water–uracil complexes, which we compared with the structurally similar chloride-tetracyanobenzene (TCB) complex previously shown to contain a strong charge-transfer (CT) binding component. We demonstrate that the CT component in lp–π interactions between water and indole/uracil is significantly smaller than that stabilizing the Cl-–TCB reference system. The strong lp(Cl-)–π(TCB) orbital interaction is characterized by a small energy gap and an efficient lp–π* overlap. In contrast, in lp–π interactions between water and indole or uracil, the corresponding energy gap is larger and the overlap less efficient. As a result, water–uracil and water–indole interactions are weak forces composed by smaller contributions from all energy components: electrostatics, polarization, dispersion, and charge transfer. In addition, indole exhibits a negative electrostatic potential at its π-face, making lp–π interactions less favorable than O–H...π hydrogen bonding. Consequently, some of the water–tryptophan contacts observed in X-ray structures of proteins and previously interpreted as lp–π interactions [Luisi, et al., Proteins, 2004, 57, 1–8], might in fact arise from O–H...π hydrogen bonding.
Repetitive guanine-rich nucleic acid sequences play a crucial role in maintaining genome stabilit... more Repetitive guanine-rich nucleic acid sequences play a crucial role in maintaining genome stability and the cell life cycle and represent potential targets for regulatory drugs. Recently, it has been demonstrated that guanine-based ligands with a porphyrin core can be used as markers of G-quadruplex assemblies in cell tissues. Herein, model systems of guanine-based ligands are explored by DFT methods. The energies of formation of modified guanine tetrads and those of modified tetrads stacked on the top of natural guanine tetrads have been calculated. The interaction energy has been decomposed into contributions from hydrogen bonding, stacking, and ion coordination and a twist–rise potential energy scan has been performed to find the individual local minima. Energy decomposition analysis reveals the impact of various substituents (F, Cl, Br, I, Me, NMe2) on individual energy terms. In addition, cooperative reinforcement in forming the modified and stacked tetrads, as well as the frontier orbitals participating in the hydrogen-bonding framework involving the HOMO–LUMO gap between the occupied s HOMO on the proton-accepting C=O and =N- groups and unoccupied s LUMO on the N-H groups, has been studied. The investigated systems are demonstrated to have a potential in ligand development, mainly due to stacking enhancement compared with natural guanine, which is used as a reference.
Ruthenium-based compounds are potential candidates for use as anticancer metallodrugs. The centra... more Ruthenium-based compounds are potential candidates for use as anticancer metallodrugs. The central ruthenium atom can be in the oxidation state +2 (e.g., RAPTA, RAED) or +3 (e.g., NAMI, KP). In this study we focus on paramagnetic NAMI analogs of a general structure [4-R-pyH] + trans-[Ru III Cl 4 (DMSO)(4-R-py)] − , where 4-R-py stands for a 4-substituted pyridine. As paramagnetic systems are generally considered difficult to characterize in detail by NMR spectroscopy, we performed a systematic structural and methodological NMR study of complexes containing variously substituted pyridines. The effect of the paramagnetic nature of these complexes on the 1 H and 13 C NMR chemical shifts was systematically investigated by temperature-dependent NMR experiments and density-functional theory (DFT) calculations. To understand the electronic factors influencing the orbital (δ orb , temperature-independent) and paramagnetic (δ para , temperature-dependent) contributions to the total NMR chemical shifts, a relativistic two-component DFT approach was used. The paramagnetic contributions to the 13 C NMR chemical shifts are correlated with the distribution of spin density in the ligand moiety and the 13 C isotropic hyperfine coupling constants, A iso (13 C), for the individual carbon atoms. To analyze the mechanism of spin distribution in the ligand, the contributions of molecular spin−orbitals (MSOs) to the hyperfine coupling constants and the spatial distribution of the z-component of the spin density in the MSOs calculated at the relativistic four-component DFT level are discussed and rationalized. The significant effects of the substituent and the solvent on δ para , particularly the contact contribution, are demonstrated. This work should contribute to further understanding of the link between the electronic structure and the NMR chemical shifts in open-shell systems, including the ruthenium-based metallodrugs investigated in this account.
Substituted coronenes, a family of ion-π receptors whose ion-affinities can be explained exclusiv... more Substituted coronenes, a family of ion-π receptors whose ion-affinities can be explained exclusively neither via ion-quadrupole nor induction/polarization mechanisms, are studied. The best descriptors of ion-affinity among these species are those characterizing charge-transfer between ions and the π-systems, e.g. vertical ionization potential, electron affinity, and the relative energies of charge-transfer excited-states (CTESs). The variation of the electric multipole moments, polarizability, binding energy, and relative energy of CTESs in the presence of an external electric field (EEF) is evaluated. The results indicate that the EEF has a negligible effect on the polarizability and quadrupole moment of the systems. However, it significantly affects the binding energies, CTES energies, and the dipole moments of the receptors. Contrary to the changes in the dipole moment, the variation pattern of the binding energy is more consistent with the pattern observed for the CTES energy changes. Finally, by analyzing the exchange-correlation component of the binding energy we demonstrate that the increased binding energy, i.e. bond strengthening, originates from enhanced electron sharing and multi-center covalency between the ions and the π-systems as a result of the state-mixing between the ground-state and the CTESs. According to our findings, we hypothesize that the electron sharing and in extreme cases the multi-center covalency are the main driving forces for complexation of ions with extended π-receptors such as carbon nano-structures.
On the basis of four-component relativistic DFT calculations, large relativistic spin−orbit effec... more On the basis of four-component relativistic DFT calculations, large relativistic spin−orbit effects amounting to more than 200 ppm for 13C and more than 1000 ppm for 29Si are identified to be the main contributions to high-frequency 13C and 29Si NMR chemical shifts in Tl(I) and Pb(II) compounds. Origin of the large SO deshielding is traced to highly efficient 6p−6p* orbital magnetic couplings.
The influence of various sugar-residue modifications on intrinsic energetic, conformational, and ... more The influence of various sugar-residue modifications on intrinsic energetic, conformational, and mechanical properties of 2´-deoxyribonucleotide-5´-monophosphates (dNs) was comprehensively investigated using modern quantum chemical approaches. In total, fourteen sugar modifications, including double bonds and heteroatoms (S, N) inside the sugar ring, as well as fluorination in various positions, were analyzed. Among hundreds of possible conformational states of dNs, only two - AI and BI, corresponding to the most biologically significant forms of a double-helical DNA, were considered for each dN. It was established that the most of the studied modifications tend to strongly stabilize either AI or BI conformation of dNs both in the gas phase and in aqueous solution (modeled by implicit solvent models). Therefore, some of these modifications can be used as a tool for reducing structural polymorphism of nucleic acids in solution as well as for designing oligonucleotides with specific structural features. The evaluation of relaxed force constants (RFC) for glycosidic bonds suggests that the majority of the studied modifications of the sugar residue yield increased strengths of glycosidic bonds in dNs, and can therefore be used for designing modified nucleic acids with an increased resistance to abasic lesions. The most significant reinforcement of the glycosidic bond occurs in dNs containing the CF2 group instead of the O4' oxygen and the fluorine atom at the 2'-alpha-position. The calculation of the RFC and vibrational root-mean-square (VRMS) deviations for conformational degrees of freedom revealed a strong dependence between mechanical properties of dNs and their energetic characteristics. In particular, electronic energies of AI and BI conformers of dNs calculated in vacuo are closely connected with the values of relaxed force constants (RFC) for the delta angle: the higher RFC(delta) values correspond to more energetically favorable conformers.
Exploring the nature of anion-π bonding by means of the Quantum Theory of Atoms in Molecules (QTA... more Exploring the nature of anion-π bonding by means of the Quantum Theory of Atoms in Molecules (QTAIM) and an energy decomposition scheme on the basis of Interacting Quantum Atoms (IQA) theory led us to conclude that these non-classical interactions benefit from “multi-center covalency” far more than from the electrostatics. Comparing to a number of closely related covalent anion-σ complexes reveals that the anion-π systems benefit from an extensive degree of electron sharing between the anions and all atoms of the π-rings. Besides, decomposition of the binding energy into classical (electrostatics) and non-classical (exchange-correlation) components demonstrates that in contrast to previous reports, the anion-π complexes are local minima, if and only if the non-classical contribution to binding energy surpasses that of the electrostatics. This suggests that the stable anion-π complexes with the anions atop the π-rings might be prepared with π-systems that benefit more from the exchange-correlation term, such as extended π-systems, but not with strong electrostatic π-receptors. This conclusion is in line with the tendency of strong π-acids to form the σ-complexes with more covalent character instead of the electrostatic π-complexes.
Intrinsic structural features and energetics of nucleotides containing variously fluorinated suga... more Intrinsic structural features and energetics of nucleotides containing variously fluorinated sugars as potential building blocks of DNA duplexes and quadruplexes are explored systematically using the modern methods of density functional theory (DFT) and quantum chemical topology (QCT). Our results suggest that fluorination at the 2′-β or 2′-α,β positions somewhat stabilizes in vacuo the AI relative to the BI conformations. In contrast, substitution of the CF2 group for the O4′ atom (O4′-CF2 modification) leads to a preference of the BI relative to AI DNA-like conformers. All the studied modifications result in a noticeable increase in the stability of the glycosidic bond [estimated by the relaxed force constants (RFC) approach], with particularly encouraging results for the O4′-CF2 derivative. Consequently, the O4′-CF2 modified systems are suggested and explored as promising scaffolds for the development of duplex and quadruplex structures with reduced propensity to form abasic lesions and to undergo DNA damage.
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Papers by Radek Marek