Biomedical subjects

Jerzy Leszczynski

Publications and source records attributed to Jerzy Leszczynski.

At least 19 recordsLinked to original sources

PubMed2006

Mechanism of action of anticancer titanocene derivatives: an insight from quantum chemical calculations.

Titanocene derivatives exhibit high potential in the treatment of cisplatin-resistant tumor types. Density functional theory calculations were performed on the hydrated form of five drug candidates differing in the pendant arms attached to the aromatic rings. A qualitative correlation has been found between the experimentally measured anticancer activity of alkylammonium-functionalized titanocene derivatives and the computed free energy change of the proton-induced dissociation reaction of these compounds. The results indicate that differences in the cytotoxic activities could be related to the solvation properties of the protolysis products, whereas no correlation was found with gas-phase properties of these molecules. Contrary to the free energy change of the protolysis reaction, other molecular properties, such as the geometrical parameters or the binding energies of the cyclopentadienyl rings in solution, do not correlate with the in vitro cytotoxic activity of these drug candidates.

Antineoplastic Agents↗

PubMed2006

Near-UV resonant two-photon ionization spectroscopy of gas phase guanine: evidence for the observation of three rare tautomers.

In light of a recently published study on the IR spectroscopy of guanine in He droplets (Choi, M. Y.; Miller, R. E. J. Am. Chem. Soc. 2006, 128, 7320), the present letter proposes a new interpretation of the resonant two-photon ionization (R2PI) experiments on gas phase guanine, which is supported by quantum chemistry calculations. Whereas He droplet experiments detect the most stable forms, only one of these forms is observed (very marginally) in the R2PI spectrum, which is actually dominated by three less stable "rare" tautomers, whose stabilities lie in the 3-7 kcal/mol range. The absence of the most stable forms in the R2PI spectrum suggests that a tautomer-dependent ultrafast relaxation process takes place in the excited state of these stable tautomers. The present reinterpretation modifies qualitatively the picture of the excited state of guanine tautomers and should contribute to the understanding of the deactivation mechanisms taking place in the excited state of DNA bases.

Gases↗

PubMed2006

Properties of the halogen-hydride interaction: an ab initio and "atoms in molecules" analysis.

X-Cl...H-Y interactions are analyzed by applying ab initio methods as well as the Bader theory. All calculations were performed using Pople's basis sets (6-311++G(2df,2pd) and 6-311++G(3df,3pd)) as well as the Dunning-type bases (aug-cc-pVDZ and aug-cc-pVTZ) within the MP2 method. For the complexes analyzed here, X-Cl and H-Y may be treated as a Lewis acid and a Lewis base, respectively. The Cl...H interactions are rather weak or at most moderate since, for the strongest interaction of the F3...HLi complex, the binding energy calculated at the MP2/6-311++G(3df,3pd) level of approximation amounts to -3.4 kcal/mol, and the H...Cl distance is equal to 2.65 A, less than the corresponding sum of van der Waals radii. These interactions may be classified as halogen-hydride interactions. However, some of the complexes analyzed, especially F3SiCl...HBeF and F3SiCl...HBeF, are very weakly bound, probably by typical van der Waals interactions.

Journal Article↗

PubMed2006

Comprehensive study of the effects of methylation on tautomeric equilibria of nucleic acid bases.

Minor tautomers of nucleic acid bases can result by intramolecular proton transfer. These rare tautomers could be stabilized through the addition of methyl groups to DNA bases. A comprehensive theoretical study of tautomers of methylated derivatives of guanine, adenine, cytosine, thymine, and uracil was performed. Molecular geometries of all tautomers were obtained at the density functional theory and MP2 levels with the 6-31G(d,p) basis set, and single-point calculations were performed at the CCSD(T)/6-311G(d,p) level. Tautomers obtained by protonation at the preferred protonation site for methylated isolated bases were compared to their nonmethylated counterparts. The effects of methylation on the relative stabilities of nucleic acid base tautomers are also studied and discussed in this work. The results suggest that some sites on the bases may not be mutagenic and may even stabilize the canonical Watson-Crick form. The results also indicate that a number of methylation sites can stabilize the tautomers, suggesting possible mechanisms for mutagenic changes.

Computer Simulation↗

PubMed2006

Toward a reversible isolation of a C20 fullerene inside a tetraureacalix[4]arene dimer. A theoretical study.

The potential stabilization of normally unstable C20, the smallest fullerene, via its encapsulation inside a tetraureacalix[4]arene dimer has been analyzed using molecular mechanics calculations with different force fields, the self-consistent-charge density-functional tight-binding with dispersion correction (SCC-DFTB-D) model, and standard density-functional-theory (DFT) calculations. The interaction energies obtained for the C20 complex have been compared with analogous values calculated for numerous complexes of the tetraureacalix[4]arene dimer with other guests. Results of the calculations with all force fields and SCC-DFTB-D predict that the binding of C20 occurs with the highest selectivity. On the other hand, standard DFT calculations fail to correctly describe the stabilization of the complexes under study as standard DFT generally does not treat dispersion interactions properly. Predicted relative stabilities of the complexes are discussed in conjunction with available experimental data. Molecular dynamics simulations reveal the instability of the guest-free capsular dimer, which decomposes on a 1-ns time scale, while dimeric complexes with guests remained intact during the 5-ns simulation time, indicating the guest-driven formation of the molecular capsule.

Journal Article↗

PubMed2006

Electron attachment-induced DNA single strand breaks: C3'-O3' sigma-bond breaking of pyrimidine nucleotides predominates.

A detailed understanding of DNA strand breaks induced by low energy electrons (LEE) is of crucial importance for the advancement of many areas of molecular biology and medicine. To elucidate the mechanism of DNA strand breaks by LEEs, theoretical investigations of the electron attachment-induced C3'-O3' sigma-bond breaking of the pyrimidine nucleotides have been performed. Calculations of 2'-deoxycytidine-3'-monophosphate and 2'-deoxythymidine-3'-monophosphate in their protonated form (denoted as 3'-dCMPH and 3'-dTMPH) have been carried out with the reliably calibrated B3LYP/DZP++ theoretical approach. Our results demonstrate that the transfer of the negative charge from the pi*-orbital of the radical anion of pyrimidines to the DNA backbone does not pass through the N1-glycosidic bond. Instead, the migration of the excessive negative charge through the atomic orbital overlap between the C6 of pyrimidine and the C3' of ribose most likely represents a pathway that subsequently leads to the strand breaks. The proposed mechanism of the LEE-induced single strand breaks in DNA assumes that the formation of the base-centered radical anions is the first step in this process. Subsequently, these electronically stable radical anions may undergo either C-O bond breaking or N-glycosidic bond rupture. The present investigation of 3'-dCMPH and 3'-dTMPH yields an energy barrier of 6.2-7.1 kcal/mol for the C3'-O3' sigma-bond cleavage. This is much lower than the energy barriers required for the C5'-O5' sigma-bond and the N1-glycosidic bond break. Therefore, we conclude that the C3'-O3' sigma-bond rupture dominates the LEE-induced single strand breaks of DNA.

Carbon↗

PubMed2006

Molecular basis of the recognition process: hydrogen-bonding patterns in the guanine primary recognition site of ribonuclease T1.

Investigation of the intrinsic H-bonding pattern of the guanine complex with a sizable segment (from Asn43 to Glu46) of the primary recognition site (PRS) in RNase T1 at the B3LYP/6-311G(d,p) level of theory enables the electronic density characteristics of the H-bonding patterns of the guanine-PRS complexes to be identified. The perfect H-bonding pattern in the guanine recognition site is achieved through the guanine complex interactions with the large segment of the PRS. Two significant short H-bonds, O epsilon 1...HN1 and O epsilon 2...HN2, have been identified. The similar short H-bond distances found in the anionic GC- base pair and in this study suggest that the short hydrogen-bond distances may be characteristic of the multiple H-bonded anionic nucleobases. The H-bonding energy distribution, the geometric analysis of the H-bonding pattern, and the electron structure characteristics of the H-bonds in the guanine PRS of RNase T1 all suggest that the O epsilon 1...HN1 and O epsilon 2...HN2 side-chain H-bonds dominate the binding at the guanine recognition site of RNase T1. Also, the geometry evidence, the electron structure characteristics, and the properties of the bond critical points of the H-bonds reveal that the side-chain H-bonding and the main-chain H-bonding are mutually intensifying. Thus the positive cooperativity between Asn43 to Tyr45 and Glu46 is proposed.

Binding Sites↗

PubMed2006

Probing the acetylcholinesterase inhibition of sarin: a comparative interaction study of the inhibitor and acetylcholine with a model enzyme cavity.

Interaction energies have been estimated between sarin and a model enzyme cavity of acetylcholinesterase (ACHE) using the density functional and Møller-Plesset second-order perturbation (MP2) levels of theories. The calculated interaction energies have been compared with those of acetylcholine and the same model ACHE cavity. The ACHE...sarin and ACHE...acetylcholine (Ach) structures have been optimized using DFT based two-layer ONIOM hybrid calculations. The nature of interactions has been investigated in detail using an interaction energy partitioning technique. The effects of solvation on the interaction energies have also been taken into account. An inhibition mechanism during the uptake of sarin inside the ACHE cavity has been proposed from the comparison of the energetics of the ACHE...sarin and ACHE...Ach complexes.

Acetylcholine↗

PubMed2006

Influence of microhydration on the ionization energy thresholds of thymine: comparisons of theoretical calculations with experimental values.

In the present study the ionization energy thresholds (IETs) of thymine, and thymine keto-enol tautomers, have been calculated (with the B3LYP, and P3 levels of theory using the standard 6-31++G(d,p) basis set) with 1-3 water molecules placed in the first hydration shell. Calculations show there is a distinct effect of microhydration on the IET of thymine. The first water molecule is seen to decrease the IET by about 0.1 eV, whereas the second and third water molecules cause a further decrease of less than 0.1 eV each. The changes in IET calculated here for thymine with 1-3 waters of hydration are smaller than the experimental values determined by Kim et al. (J. Phys. Chem. 1996, 100, 7933). Therefore calculations have been performed on the microhydrated keto-enol tautomers of thymine. The calculated results on the keto-enol tautomers are seen to be in better agreement with the experimental results. However, the keto-enol thymine tautomers are considerably higher in energy than the canonical form of thymine, and there is presently no good evidence that these thymine tautomers are actually present in a supersonic jet-cooled experiment.

Computer Simulation↗

PubMed2006

Mass spectrometric and quantum chemical studies of the thermodynamics and bonding of neutral and ionized LnCl, LnCl2, and LnCl3 species (Ln = Ce, Lu).

The mass spectral patterns of CeCl3(g) and LuCl3(g) and appearance energies for the identified ions were measured using a Nier-type mass spectrometer coupled with a Knudsen cell. The molecular ion CeCl3+ was found to be considerably less stable in comparison to LuCl3+. Partial pressures and sublimation enthalpies of LnCl3(s) to monomeric LnCl3(g) and dimeric Ln2Cl6(g) species were obtained in the ranges of 882-1028 (Ln = Ce) and 850-1004 K (Ln = Lu). The contribution of dimeric Ce2Cl6(g) species to equilibrium vapors of CeCl3(s) is considerably smaller than the Lu2Cl6(g) contribution in LuCl3(s) vapors. The measurements were supplemented by quantum chemical ab initio studies of structures, energetics, and vibrational frequencies of neutral and singly ionized LnCl, LnCl2, and LnCl3 species (Ln = Ce, Lu). The theoretical appearance energies of different ions, calculated from the energies of the gaseous species, are in good agreement with experimental data. The fragmentation energies of LnCl, LnCl2, and LnCl3 were also computed and compared with the mass spectral patterns of respective vapor species. The Mulliken and natural bond orbital electron population methods were applied for the systematic analysis of the bonding scheme in molecules and cations.

Journal Article↗

PubMed2006

Cooperativity in hydrogen-bonded interactions: ab initio and "atoms in molecules" analyses.

The H(2)CO...(HF)(n) (n = 1, ..., 9) complexes were investigated using the MP2 method and the following basis sets: 6-311++G(d,p), aug-cc-pVDZ and aug-cc-pVTZ. It was found that the cooperativity effect enhances significantly the F-H...O hydrogen bond; in some of cases one can detect the covalent nature of hydrogen bonding. To deepen the nature of the interactions investigated, the scheme of decomposition of the interaction energy was applied; for stronger H-bonds where the cooperativity is more important, the delocalization energy term increases. The ratio of delocalization energy to electrostatic energy increases for stronger hydrogen bonds where the proton...acceptor distance is shorter. The Bader theory was also applied, and it was found that for stronger H-bonds the electronic energy density at the proton...acceptor bond critical point is negative and may be attributed to the partly covalent interaction.

Algorithms↗

PubMed2006

Structure-toxicity relationships of nitroaromatic compounds.

The toxicity data of 28 nitroaromatic compounds (nitrobenzenes and, for comparison, benzene and toluene) related to a 50% lethal dose concentration for rats (LD50) were used to develop quantitative structure-activity relationships (QSARs).A genetic algorithm and multiple regression analysis were applied to select the descriptors and to generate the correlation models. The obtained equations consist of one to three descriptors. A number of molecular descriptors was obtained from HF/6-31G(d) and DFT (B3LYP/6-311+G(d, p)) level calculations. The calculated molecular geometry and electronic properties were evaluated by comparison with the available experimental data (where applicable). All parameters obtained at the B3LYP/6-311+G(d, p) level and the topological descriptors derived from this geometry were found to be reliable, except for dipole moment, due to the large uncertainty of its estimation. Satisfactory relationships were observed for the one-parameter structure-toxicity models between topological (X5Av, Ms) and quantum-chemical (ELUMO) descriptors. For better predictability two- and three-parameter QSAR analyses were performed. These analyses resulted in much better equations with correlation coefficient values r = 0.872-0.924. These models have been obtained with a set of topological, fragment and quantum-chemical descriptors (Ms, PCR, PCD, BELe1, C-026 and ELUMO). The toxicity of nitroaromatic compounds appears to be governed by a number of factors, such as the number of nitrogroups, the electrotopological state, the presence of certain fragments and the electrophilicity/reactivity parameter (ELUMO). Nitrobenzenes exhibited electrophilic reactivity (as was shown by correlation of the toxicity with the energy of the lowest unoccupied orbital, ELUMO). The toxicity LD50 parameter for rats has been utilized for the first time for QSAR analysis of nitrobenzenes. The predictive ability of the models is determined by a cross-validation "leave-one-out" method.

Animals↗

PubMed2006

Physical nature of ethidium and proflavine interactions with nucleic acid bases in the intercalation plane.

On the basis of the crystallographic structures of three nucleic acid intercalation complexes involving ethidium and proflavine, we have analyzed the interaction energies between intercalator chromophores and their four nearest bases, using a hybrid variation-perturbation method at the second-order Møller-Plesset theory level (MP2) with a 6-31G(d,p) basis set. A total MP2 interaction energy minimum precisely reproduces the crystallographic position of the ethidium chromophore in the intercalation plane between UA/AU bases. The electrostatic component constitutes the same fraction of the total energy for all three studied structures. The multipole electrostatic interaction energy, calculated from cumulative atomic multipole moments (CAMMs), was found to converge only after including components above the fifth order. CAMM interaction surfaces, calculated on grids in the intercalation planes of these structures, reasonably reproduce the alignment of intercalators in crystal structures; they exhibit additional minima in the direction of the DNA grooves, however, which also need to be examined at higher theory levels if no crystallographic data are given.

Algorithms↗

PubMed2006

Theoretical study of interaction of urate with li(+), na(+), k(+), be(2+), mg(2+), and ca(2+) metal cations.

The geometries and energetics of complexes of Li(+), Na(+), K(+), Be(2+), Mg(2+), and Ca(2+)metal cations with different possible uric acid anions (urate) were studied. The complexes were optimized at the B3LYP level and the 6-311++G(d,p) basis set. Complexes of urate with Mg(2+), and Ca(2+)metal cations were also optimized at the MP2/6-31+G(d) level. Single point energy calculations were performed at the MP2/6-311++G(d,p) level. The interactions of the metal cations at different nucleophilic sites of various possible urate were considered. It was revealed that metal cations would interact with urate in a bi-coordinate manner. In the gas phase, the most preferred position for the interaction of Li(+), Na(+), and K(+) cations is between the N(3) and O(2) sites, while all divalent cations Be(2+), Mg(2+), and Ca(2+) prefer binding between the N(7) and O(6) sites of the corresponding urate. The influence of aqueous solvent on the relative stability of different complexes has been examined using the Tomasi's polarized continuum model. The basis set superposition error (BSSE) corrected interaction energy was also computed for complexes. The AIM theory has been applied to analyze the properties of the bond critical points (electron densities and their Laplacians) involved in the coordination between urate and the metal cations. It was revealed that aqueous solvation would have significant effect on the relative stability of complexes obtained by the interaction of urate with Mg(2+) and Ca(2+)cations. Consequently, several complexes were found to exist in the water solution. The effect of metal cations on different NH and CO stretching vibrational modes of uric acid has also been discussed.

Algorithms↗

PubMed2006

The possible covalent nature of N-H...O hydrogen bonds in formamide dimer and related systems: an ab initio study.

The N-H...O hydrogen bonds are analyzed for formamide dimer and its simple fluorine derivatives representing a wide spectrum of more or less covalent interactions. The calculations were performed at the MP2/6-311++G(d,p) level of approximation. To explain the nature of such interactions, the Bader theory was also applied, and the characteristics of the bond critical points (BCPs) were analyzed: the electron density at BCP and its Laplacian, the electron energy density at BCP and its components, the potential electron energy density, and the kinetic electron energy density. These parameters are used to justify the statement that some of the interactions analyzed are partly covalent in nature. An analysis of the interaction energy components for the systems considered indicates that the covalent character of the hydrogen bond is manifested by a markedly increased contribution of the delocalization term relative to the electrostatic interaction energy. Moreover, the ratio of stabilizing the delocalization/electrostatic contributions grows linearly with the decreasing lengths of the hydrogen bond.

Journal Article↗

PubMed2006

Phosphonylation mechanisms of sarin and acetylcholinesterase: a model DFT study.

Potential energy surfaces for the phosphonylation of sarin and acetylcholinesterase (AChE) have been theoretically studied at the B3LYP/6-311G(d,p) level of theory. The obtained results show that the phosphonylation process involves a two-step addition-elimination mechanism, with the first step (addition process) being the rate-determining step, while by comparison, the ensuing steps are very rapid. Stable trigonal bipyramidal intermediates are formed in the studied pathways. It is also revealed that the catalytic triad of acetylcholinesterase plays the catalytic role in the reaction by speeding up the phosphonylation process, as it does in the acylation reaction of ACh and AChE. The effect of aqueous solvation was accounted for via the polarizable continuum model. It is concluded that the enzymatic reaction here is influenced strongly by the solvent environment.

Acetylcholinesterase↗

PubMed2006

DNA strand breaks induced by near-zero-electronvolt electron attachment to pyrimidine nucleotides.

To elucidate the mechanism of DNA strand breaks by low-energy electrons (LEE), theoretical investigations of the LEE attachment-induced C(5')-O(5') sigma bond breaking of pyrimidine nucleotides (5'-dCMPH and 5'-dTMPH) were performed by using the B3LYP/DZP++ approach. The results indicate that the pyrimidine nucleotides are able to capture electrons characterized by near-0-eV energy to form electronically stable radical anions in both the gas phase and aqueous solution. The mechanism of the LEE-induced single-strand bond breaking in DNA might involve the attachment of an electron to the bases of DNA and the formation of base-centered radical anions in the first step. Subsequently, these radical anions undergo either C-O or glycosidic bond breaking, yielding neutral ribose radical fragments and the corresponding phosphoric anions or base anions. The C-O bond cleavage is expected to dominate because of its low activation energy. In aqueous solutions, the significant increases in the electron affinities of pyrimidine nucleotides ensure the formation of electronically more stable radical anions of the nucleotides. The low activation energy barriers for the C(5')-O(5') bond breaking predicted in this work are relevant when the counterions are close enough to the phosphate moiety of DNA.

DNA↗

PubMed2006

Heteronuclear intermolecular resonance-assisted hydrogen bonds. The structure of pyrrole-2-carboxamide (PyCa).

The crystal and molecular structure of pyrrole-2-carboxamide (PyCa) determined by single crystal X-ray diffraction is presented. Molecular conformations of PyCa are also analyzed by FT-IR and NMR techniques. Additionally DFT calculations at the B3LYP/6-311++G(d,p) level of approximation are performed for dimers of PyCa and for related species. The existence of two tautomeric forms for the analyzed dimers differing in H-bond motifs, N-H...O or O-H...N, is studied. The geometrical and energetic features of such H-bonds show that these interactions may be classified as intermolecular resonance-assisted hydrogen bonds. Additionally the Bader theory is applied to determine and to analyze bond critical points.

Journal Article↗