Biomedical subjects

A Liwo

Publications and source records attributed to A Liwo.

At least 37 records · Page 2Linked to original sources

PubMed1997

Design of a knowledge-based force field for off-lattice simulations of protein structure.

Prediction of protein structure from amino-acid sequence still continues to be an unsolved problem of theoretical molecular biology. One approach to solve it is to construct an appropriate (free) energy function that recognizes the native structures of some selected proteins (whose native structures are known) as the ones distinctively lowest in (free) energy and then to carry out a search of the lowest-energy structure of a new protein. In order to reduce the complexity of the problem and the cost of energy evaluation, the so-called united-residue representation of the polypeptide chain is often applied, in which each amino-acid residue is represented by only a few interaction sites. Once the global energy minimum of the simplified chain has been found, the all-atom structure can easily and reliably be constructed. The search of the lowest-energy structure is usually carried out by means of Monte Carlo methods, though use of more efficient global-optimization methods, especially those of deformation of original energy surface is potentially promising. Monte Carlo search of the conformational space can be accelerated greatly, if the chain is superposed on a discrete lattice (the on-lattice approach). On the other hand, the on-lattice approach prohibits the use of many efficient global-optimization methods, because they require both energy and its space derivatives. The on-lattice methods in which the chain is embedded in the continuous 3D space are, therefore, also worth developing. In this paper we summarize the work on the design and implementation of an off-lattice united-residue force field that is underway in our group, in cooperation with Professor HA. Scheraga of Cornell University, U.S.A.

Models, Molecular↗

PubMed1996

Coupling between folding and ionization equilibria: effects of pH on the conformational preferences of polypeptides.

A new approach to the conformational study of polypeptides is presented. It considers explicitly the coupling between the conformation of the molecule and the ionization equilibria at a given pH value. Calculations of the solvation free energy and free energy of ionization of a 17-residue polypeptide are carried out using a fast multigrid boundary element method (MBE). The MBE method uses an adaptive tessellation of the molecular surface by boundary elements with non-regular size to solve the Poisson equation rapidly, and with a high degree of accuracy. The MBE method is integrated into the ECEPP (Empirical Conformational Energy Program for Peptides) algorithm to compute the coupling between the ionization state and the conformation of the molecule. This approach has been applied to study the conformational preference of a short polypeptide for which the available NMR and CD experimental data indicate that conformations containing a right-handed alpha-helical segment are energetically more favorable at low values of pH. The results of calculations using the present method agree quite well with experiments, in contrast to previous applications with standard techniques (using pre-assigned charges at each pH) that were not able to reproduce the experimental findings. Also, it is shown how the coupling to the conformation leads to different degrees of ionization of a given type of residue, for example glutamic acid, at different positions in the amino acid sequence, at any given pH. The results of this study provide a sound basis to discuss the origin of the stability of polypeptide conformations, and its dependence on the environmental conditions.

Computer Simulation↗

PubMed1996

Theoretical prediction of a crystal structure.

The diffusion equation method of global minimization is applied to compute the crystal structure of S6, with no a priori knowledge about the system. The experimental lattice parameters and positions and orientations of the molecules in the unit cell are predicted correctly.

Journal Article↗

PubMed1996

Fluorescence and Monte Carlo conformational studies of the (1-15) galanin amide fragment.

Galanin (GAL) is a 29 amino acid C-terminally aminated linear neuropeptide showing diverse biological activities. The N-terminal (1-15)GAL-NH2 fragment was shown to have a very high affinity to the galanin receptor. In this work we describe the results of a combined fluorescence and Monte Carlo studies, the latter carried out using the ECEPP/3 force field with and without including hydration, on the (1-15)GAL-NH2 fragment. Using the time-domain technique we measured fluorescence decay times of the tyrosine residue in position 9. Based on the Forster energy transfer theory we calculated the distance and distance distribution between the Trp2 (acceptor) and Tyr9 (donor) aromatic side chains. The distance obtained was about 10.5 angstrom and half-width, hw, of the distance distribution was 5.6 angstrom. This results were found to be in good agreement with the chromophore distances calculated for the low-energy solution confirmations obtained in Monte Carlo simulations. All the low-energy conformations obtained in the absence of water were almost all-helical with the exception of a few C-terminal residues. In contrast, none of the low-energy solution conformations contained any significant amount of secondary structure. These findings are in agreement with the results of earlier CD and NMR conformational studies of galanin in water and non-aqueous solvents. On the other hand, the conformations obtained in the presence of water turned out to be largely compact in the N-terminal hydrophobic part. This explains the relatively short distance between chromophores and narrow distance distribution obtained in fluorescence measurements.

Amides↗

PubMed1996

Exploration of the conformational space of oxytocin and arginine-vasopressin using the electrostatically driven Monte Carlo and molecular dynamics methods.

Conformational analysis of the neurohypophyseal hormones oxytocin (OT) and arginine-vasopressin (AVP) has been carried out using two different computational approaches and three force fields, namely by the Electrostatically Driven Monte Carlo (EDMC) method, with the Empirical Conformational Energy Program for Peptides (ECEPP/3) force field or with the ECEPP/3 force field plus a hydration-shell model, and by simulated-annealing molecular dynamics with the Consistent Valence Force Field (CVFF). The low-energy conformations obtained for both hormones were classified using the minimal-tree clustering algorithm and characterized according to the locations of beta-turns in the cyclic moieties. Calculations with the CVFF force field located conformations with a beta-turn at residues 3 and 4 as the lowest energy ones both for OT and for AVP. In the ECEPP/3 force field the lowest energy conformation of OT contained a beta-turn at residues 2 and 3, conformations with this location of the turn being higher in energy for AVP. The latter difference can be attributed to the difference in the size of the side chain in position 3 of the sequences: the bulkier phenylalanine residue of AVP in combination with the bulky Tyr2 residue hinders the formation of a turn at residues 2 and 3. Conformations of OT and AVP with a turn at residues 3,4 were in the best agreement with the x-ray structures of deaminooxytocin and pressinoic acid (the cyclic moiety of vasopressin), respectively, and with the nmr-derived distance constraints. Generally, the low-energy conformations obtained with the hydration-shell model were in a better agreement with the experimental data than the conformations calculated in vacuo. It was found, however, that the obtained low-energy conformations do not satisfy all of the nmr-derived distance constraints and the nuclear Overhauser effect pattern observed in nmr studies can be fully explained only by assuming a dynamic equilibrium between conformations with beta-turns at residues 2,3, 3,4, and 4,5. The low-energy structures of OT with a beta-turn at residues 2,3 have the disulfide ring conformations close to the model proposed recently for a potent bicyclic antagonist of OT [M. D. Shenderovich et al. (1994) Polish Journal of Chemistry, Vol. 25, pp. 921-927], although the native hormone differs from the bicyclic analogue by the conformation of the C-terminal tripeptide. This finding confirms the hypothesis of different receptor-bound conformations of agonists and antagonists of OT.

Amino Acid Sequence↗

PubMed1995

Theoretical conformational analysis of three vasopressin antagonists with a modified cyclohexyl ring in the first thioacid residue.

Analogues of arginine vasopressin (AVP) with bulky thioacid residues in position 1 of the amino acid sequence are known to be effective antagonists of the pressor response. Some of the most effective ones are those that have the first cysteine residue replaced with beta,beta-cyclopentamethylene-beta'-mercaptopropionic acid (Cpp) and its derivatives, such as 4-mercapto-4-tetrahydropyraneacetic acid (OCA) and 4-mercapto-4-tetrahydrothiopyraneacetic acid (SCA). The SCA analogues are more potent and the OCA ones slightly less potent antagonists than the Cpp ones. In this study we carried out conformational calculations on [Cpp1]AVP, [OCA1]AVP and [SCA1]AVP, using the ECEPP/3 force field both with and without hydration (to simulate an aqueous and non-polar receptor environment, respectively). It was found that most of the low-energy conformations are common in geometry and relative energy for all three compounds studied. It can therefore be concluded that the modifications of the cyclohexyl ring in position 1 influence the binding to the receptor because of changing the lipophilicity of the first residue, rather than by changing the conformational space. This is further supported by the fact that the lowest-energy conformations in the absence of water have closely located the Phe3 side chain (which is critical for the interaction with vasopressin receptors) and the (modified) cyclohexyl ring. The lowest-energy conformations in the presence and absence of water had beta-turns at residues Phe3-Gln4 and Gln4-Asn5, and Gln4-Asn5, respectively. The conformation with the turn at Gln4-Asn5 was most similar to the crystal structure of the pressinoic acid (the cyclic moiety of vasopressin).

Arginine Vasopressin↗

PubMed1995

Molecular modeling of singlet-oxygen binding to anthraquinones in relation to the peroxidating activity of antitumor anthraquinone drugs.

Anthraquinone derivatives are important anti-cancer drugs possessing, however, undesirable peroxidating and, in consequence, cardiotoxic properties. This results from the mediation by these compounds of the one-electron reduction processes of the oxygen molecule, which produces the highly toxic superoxide anion radical and other active oxygen species. This article summarizes the results of our studies on the molecular aspects of the mechanism of anthraquinone-mediated peroxidation which were carried out using enzymatic-assay, electrochemical, and quantum-mechanical methods.

Anthraquinones↗

PubMed1994

Comparison of the low energy conformations of an oncogenic and a non-oncogenic p21 protein, neither of which binds GTP or GDP.

Oncogenic p21 protein, encoded by the ras-oncogene, that causes malignant transformation of normal cells and many human tumors, is almost identical in sequence to its normal protooncogene-encoded counterpart protein, except for the substitution of arbitrary amino acids for the normally occurring amino acids at critical positions such as Gly 12 and Gln 61. Since p21 is normally activated by the binding of GTP in place of GDP, it has been postulated that oncogenic forms must retain bound GTP for prolonged time periods. However, two multiply substituted p21 proteins have been cloned, neither of which binds GDP or GTP. One of these mutant proteins with Val for Gly 10, Arg for Gly 12, and Thr for Ala 59 causes cell transformation, while the other, similar protein with Gly 10, Arg 12, Val for Gly 13 and Thr 59 does not transform cells. To define the critical conformational changes that occur in the p21 protein that cause it to become oncogenic, we have calculated the low energy conformations of the two multiply substituted mutant p21 proteins using a new adaptation of the electrostatically driven Monte Carlo (EDMC) technique, based on the program ECEPP. We have used this method to explore the conformational space available to both proteins and to compute the average structures for both using statistical mechanical averaging. Comparison of the average structures allows us to detect the major differences in conformation between the two proteins. Starting structures for each protein were calculated using the recently deposited x-ray crystal coordinates for the p21 protein, that was energy-refined using ECEPP, and then perturbed using the EDMC method to compute its average structure. The specific amino acid substitutions for both proteins were then generated into the lowest energy structure generated by this procedure, subjected to energy minimization and then to full EDMC perturbations. We find that both mutant proteins exhibit major differences in conformation in specific regions, viz., residues 35-47, 55-78, 81-93, 96-110, 115-126, and 123-134, compared with the EDMC-refined x-ray structure of the wild-type protein. These regions have been found to be the most flexible in the p21 protein bound to GDP from prior molecular dynamics calculations (Dykes et al., 1993). Comparison of the EDMC-average structure of the transforming mutant with that of the nontransforming mutant reveals major structural differences at residues 10-16, 32-40, and 60-68. These structural differences appear to be the ones that are critical in activation of the p21 protein.(ABSTRACT TRUNCATED AT 400 WORDS)

Crystallography, X-Ray↗

PubMed1994

Prediction of conformation of rat galanin in the presence and absence of water with the use of Monte Carlo methods and the ECEPP/3 force field.

The conformation of the 29-residue rat galanin neuropeptide was studied using the Monte Carlo with energy minimization (MCM) and electrostatically driven Monte Carlo (EDMC) methods. According to a previously elaborated procedure, the polypeptide chain was first treated in a united-residue approximation, in order to enable extensive exploration of the conformational space to be carried out (with the use of MCM). Then the low-energy united-residue conformations were converted to the all-atom representations, and EDMC simulations were carried out for the all-atom polypeptide chains, using the ECEPP/3 force field with hydration included. In order to estimate the effect of environment on galanin conformation, the low-energy conformations obtained as a result of these simulations were taken as starting structures for further EDMC runs that did not include hydration. The lowest-energy conformation obtained in aqueous solution calculations had a nonhelical N-terminal part packed against the nonpolar face of a residual helix that extended from Pro13 toward the C-terminus. One next lowest-energy structure was a nearly-all-helical conformation, but with a markedly higher energy. In contrast, all of the low-energy conformations in the absence of water were all-helical differing only by the extent to which the helix was kinked around Pro13. These results are in qualitative agreement with the available NMR and CD data of galanin in aqueous and nonaqueous solvents.

Amino Acid Sequence↗

PubMed1994

Enthalpy of oxygen addition to anthraquinone derivatives determines their ability to mediate NADH oxidation.

Anthraquinone derivatives are important anti-cancer drugs possessing undesirable cardiotoxic properties related to their peroxidating activity. Previous studies have suggested that this activity can be caused by the binding of a singlet oxygen molecule to an anthraquinone, followed by the one-electron reduction of the complex formed, and its further dissociation into anthraquinone and the superoxide anion radical. In this study, we have carried out semi-empirical PM3 calculations of the energetics of the formation of peroxides and hydroperoxides from hydroxy, amino and imino derivatives of 9,10-anthracenedione. These calculations were supplemented with ab initio calculations, using STO-3G, 4-31G and 6-31G basis sets, on the energetics of oxygen binding to 1,4-dihydroxy and 1,4-diaminobenzene. It was found that for anthraquinones possessing hydroxyl groups, the formation of hydroperoxides is significantly favored energetically compared with the formation of peroxides. In the case of anthraquinones containing only amino groups, the formation of hydroperoxides is less favorable, owing to a greater enthalpy of amino group deprotonation compared with that of hydroxyl group. The effect of electrostatic solvation on the energetics of oxygen addition was also investigated using the Conductor-like Screening Model (COSMO) approach. The effect of solvation on peroxide formation was found to be small, while in the case of hydroperoxides solvation was found to lower the enthalpy of this reaction by approximately 10 kcal/mol for epsilon = 78 (simulating an aqueous environment). Significant stabilization of hydroperoxides was estimated in weakly polar media (epsilon = 4) which can simulate the quinone-reducing center of the mitochondrial NADH dehydrogenase. The enthalpies obtained for oxygen addition to anthraquinones involving the formation of the most stable of the peroxide and hydroperoxide species are in good correlation with the rates of NADPH oxidation stimulated by these compounds and, in turn, with their peroxidating properties. This correlation can be directly implemented in the design of non-peroxidating anthraquinone-derived anti-cancer drugs.

Anthraquinones↗

PubMed1993

Calculation of protein backbone geometry from alpha-carbon coordinates based on peptide-group dipole alignment.

An algorithm is proposed for the conversion of a virtual-bond polypeptide chain (connected C alpha atoms) to an all-atom backbone, based on determining the most extensive hydrogen-bond network between the peptide groups of the backbone, while maintaining all of the backbone atoms in energetically feasible conformations. Hydrogen bonding is represented by aligning the peptide-group dipoles. These peptide groups are not contiguous in the amino acid sequence. The first dipoles to be aligned are those that are both sufficiently close in space to be arranged in approximately linear arrays termed dipole paths. The criteria used in the construction of dipole paths are: to assure good alignment of the greatest possible number of dipoles that are close in space; to optimize the electrostatic interactions between the dipoles that belong to different paths close in space; and to avoid locally unfavorable amino acid residue conformations. The equations for dipole alignment are solved separately for each path, and then the remaining single dipoles are aligned optimally with the electrostatic field from the dipoles that belong to the dipole-path network. A least-squares minimizer is used to keep the geometry of the alpha-carbon trace of the resulting backbone close to that of the input virtual-bond chain. This procedure is sufficient to convert the virtual-bond chain to a real chain; in applications to real systems, however, the final structure is obtained by minimizing the total ECEPP/2 (empirical conformational energy program for peptides) energy of the system, starting from the geometry resulting from the solution of the alignment equations. When applied to model alpha-helical and beta-sheet structures, the algorithm, followed by the ECEPP/2 energy minimization, resulted in an energy and backbone geometry characteristic of these alpha-helical and beta-sheet structures. Application to the alpha-carbon trace of the backbone of the crystallographic 5PTI structure of bovine pancreatic trypsin inhibitor, followed by ECEPP/2 energy minimization with C alpha-distance constraints, led to a structure with almost as low energy and root mean square deviation as the ECEPP/2 geometry analog of 5PTI, the best agreement between the crystal and reconstructed backbone being observed for the residues involved in the dipole-path network.

Algorithms↗

PubMed1993

Prediction of protein conformation on the basis of a search for compact structures: test on avian pancreatic polypeptide.

Based on the concept that hydrophobic interactions cause a polypeptide chain to adopt a compact structure, a method is proposed to predict the structure of a protein. The procedure is carried out in four stages: (1) use of a virtual-bond united-residue approximation with the side chains represented by spheres to search conformational space extensively using specially designed interactions to lead to a collapsed structure, (2) conversion of the lowest-energy virtual-bond united-residue chain to one with a real polypeptide backbone, with optimization of the hydrogen-bond network among the backbone groups, (3) perturbation of the latter structure by the electrostatically driven Monte Carlo (EDMC) procedure, and (4) conversion of the spherical representation of the side chains to real groups and perturbation of the whole molecule by the EDMC procedure using the empirical conformational energy program for peptides (ECEPP/2) energy function plus hydration. Application of this procedure to the 36-residue avian pancreatic polypeptide led to a structure that resembled the one determined by X-ray crystallography; it had an alpha-helix starting at residue 13, with the N-terminal portion of the chain in an extended conformation packed against the alpha-helix. Similar structures with slightly higher energies, but looser packing, were also obtained.

Amino Acids↗

PubMed1993

A theoretical study of the mechanism of oxygen binding by model anthraquinones. Part II. Quantum-mechanical studies of the energetics of oxygen binding to model anthraquinones.

Anthracycline derivatives, which constitute an important class of antitumor drugs, exhibit undesirable cardiotoxicity owing to their mediation in the process of oxygen reduction to the superoxide anion radical. Earlier work showed that this mediation could be facilitated by the formation of complexes with the 1 delta g oxygen molecule prior to reduction. In this paper, we investigate the energetics of the possible peroxides formed by a series of model anthraquinones: 1,4-dihydroxyl- (quinizarin), 1,8-dihydroxyl-, 1-hydroxy-8-methoxy-, 1,8-dimethoxy-, 1,4,5-trimethoxy- and 1,4-dihydroxy-5-methoxy-9,10-anthracenedione, as well as of daunorubicin and demethoxydaunorubicin, by semi-empirical quantum-mechanical MNDO and PM3 methods, and limited STO-3G ab initio calculations. It was found that the oxygen-binding site is determined by three factors: the high electron density and high HOMO coefficients on the carbon atoms to which oxygen binds, the minimum loss of conjugation within the anthraquinone moiety on oxygen binding and the minimum number of bonds to other heavy atoms of the oxygen-binding carbons (the steric effect). For different molecules, the energy of the most stable oxygen complex is the greatest for compounds with the lowest ionization potential. On the basis of this and our earlier studies, it was concluded that the anthracycline derivatives with reduced ability to bind oxygen and, therefore, reduced cardiotoxicity, should possess a high symmetry of II-electron density distribution, a high ionization potential and have all of the oxygen-binding sites condensed to other rings or substituted by bulky groups.

Anthraquinones↗

PubMed1992

Effects of compact volume and chain stiffness on the conformations of native proteins.

An investigation of the statistical properties of the native conformations of proteins, observed from crystal structures, is reported. Protein conformations were analyzed in terms of a bond vector correlation function and molecular volume. It was observed that, while the volume of a protein structure varies nearly linearly with the number of residues, the bond vector correlation function exhibits a universal feature for all sizes of proteins. To interpret the nature of the bond vector correlation function of native protein structures quantitatively, Monte Carlo simulations of realistic polypeptide chains of specific but arbitrary amino acid sequence were carried out. The molecule was constrained in an ellipsoidal volume determined by its chain length, and conformations with unacceptable nonbonded contacts between different amino acid residues were excluded. The interactions within a terminally blocked single residue, which correlate two nearest-neighbor peptide groups in a chain, were taken into account by an energetically biased sampling of its phi-psi space. The simulated chain correlation functions were found to be in good agreement with those of the crystal structures of beta-sheet-type and mixed-type (alpha+beta) proteins of similar length. On the basis of these calculations, it is concluded that the observed conformations of these native proteins may arise from two basic factors: the compactness of structures under hydrophobic interactions and the intrinsic stiffness of polypeptide chains due to the interactions within each terminally blocked residue.

Biophysical Phenomena↗

PubMed1992

Investigation of the inhibition pathway of glucosamine synthase by N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid by semiempirical quantum mechanical and molecular mechanics methods.

Glucosamine synthase (E.C. 2.6.1.16) is a promising target in antifungal drug design. It has been reported that its potent inhibitor, N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP), inactivates the enzyme by the Michael addition of the S-H group to the FMDP molecule followed by cyclisation reactions. In this study we have investigated, by means of semiempirical MNDO, PM3 and molecular mechanics methods, the energetics and kinetic possibility of the formation of various stereoisomers of the products of cyclisation of the Michael addition products detected experimentally. It was found that the substituted 1,4-thiazin-3-one can be formed in one step under alkaline conditions; the stereoisomers of this compound predicted to be the most stable on the basis of theoretical calculations are also the dominant ones in reality.

Calorimetry↗

PubMed1992

A theoretical study of glucosamine synthase. II. Combined quantum and molecular mechanics simulation of sulfhydryl attack on the carboxyamide group.

Continuing our theoretical studies of glucosamine synthase catalysis, we have carried out MNDO and ab initio calculations of the first stage of the reaction, which involves the attack of a cysteine thiol group from the enzyme active site on the side chain carboxyamide group of glutamine, producing ammonia and thioester. The reactants were modelled by methyl mercaptate and acetamide, respectively. For two considered mechanisms of the reaction the energy surfaces were evaluated. Mechanism I, proposed by Chmara et al. (1985) involves the nucleophilic attack of a deprotonated thiol group on the carbonyl carbon atom. Mechanism II, postulated in our previous work (Tempczyk et al. 1989), assumes the concerted binding of the mercaptate sulphur to the carbonyl carbon and the sulfhydryl hydrogen to the amide nitrogen with simultaneous breaking of the S-H bond. The energy surface of mechanism I shows no minimum on the approach of the mercaptide anion towards the carbonyl carbon, which is also consistent with ab initio calculations in a 4-31 G basis set. Therefore, mechanism I seems to be unlikely. The same analysis of mechanism II shows that it leads to the desired products: methyl thioacetate and ammonia. The presence of a sulfhydryl hydrogen causes apparent pyramidicity of the amido nitrogen and lengthening of the C-N bond in the transition state, making conditions for the release of the ammonia molecule. The MNDO calculated energy barrier of the reaction is 50.1 kcal/mol and the approximate 4-31 G ab initio barrier (at the MNDO geometries of the substrate complex and the transition state) is 63 kcal/mol.(ABSTRACT TRUNCATED AT 250 WORDS)

Amides↗

PubMed1992

MNDO study of the mechanism of the inhibition of cysteine proteinases by diazomethyl ketones.

Diazomethyl ketones are one of the most effective irreversible inhibitors of cysteine proteinases and are therefore very important in drug design. In the present study a mechanism of inactivation is proposed based on the results of model MNDO calculations of the possible pathways. It was found that the mercaptide nucleophile, on approaching the carbonyl carbon as in the catalytic reaction path, binds to the inner diazo nitrogen. The intermediate thus formed can rearrange giving a stable product, beta-thioketone, and molecular nitrogen, with a considerable energy gain. The energy barrier to this process is equal to 36.9 kcal/mol, and corresponds to a pyramidal transition state with the vertex at the methylene carbon and the base formed by the carbonyl, thiol, and diazo groups. The energy barrier can be lowered on deprotonation of the intermediate. Based on the results obtained it was concluded that good irreversible inhibitors of cysteine proteases must fulfil two structural requirements: i) the dimensions and charge distribution must be similar to those of the peptide bond and ii) a second electrophilic center must be present in the neighbourhood of the carbonyl carbon. These are requirements which are satisfied by other strong cysteine proteinase inhibitors: beta-chloroketones and beta-ketooxiranes.

Chemical Phenomena↗

PubMed1992

A theoretical study of the mechanism of oxygen binding by model anthraquinones. I: Quantum mechanical evaluation of the oxygen-binding sites of 1,4-hydroquinone.

The undesirable cardiotoxicity of some important classes of antitumor drugs, such as anthracycline derivatives, is caused by their mediation of the one-electron reduction processes of the oxygen molecule which produces the highly toxic superoxide anion radical. Recent studies enable the conclusion to be drawn that the first and rate-limiting stage of this process is the formation of complexes of the drug anthraquinone moiety with 1 delta g molecular oxygen. The complexes can easily undergo one-electron reduction, whose product dissociates into the unchanged drug molecule and the superoxide anion radical. The present study reports quantum mechanical calculations of the structure and the energies of the possible oxygen complexes of the most simplified model compound: 1,4-benzenediol (1,4-hydroquinone); 2,3-dihydro-2,3-epidioxy-, 2,5-dihydro-2,5-epidioxy- and 1,4-epidioxy-1,4-benzenediol (the 2,3-, 2,5- and 1,4-peroxide). Calculations were carried out with the use of ab initio (STO-3G, 4-31G, and 6-31G) and semiempirical MNDO methods with total geometry optimization. The optimized geometry parameters were found to be in a reasonable agreement with the available crystal data. During the oxygen complex formation with hydroquinone, charge transfer occurs from hydroquinone to the oxygen molecule. Supplementary MNDO calculations have shown that the stability of 2,3-peroxide is increased substantially upon the ionization of one of the hydroxyl groups of hydroquinone prior to oxygen binding, which increases the electron density of the benzene ring. These findings result in a prediction that the anthracycline derivatives with electron-withdrawing substituents in the II-electron moiety should exhibit diminished affinity towards oxygen and, consequently, diminished ability to peroxidation. It has also been found that the relative energies of different peroxides are well represented even in the STO-3G ab initio calculations which will enable the further extension of the study to the complete II-electron moiety of the actual anthracycline derivatives.

Energy Transfer↗