Negative Molecular Electrostatic Potential Research Articles

Molecular Electrostatic Potential Topology Analysis of Noncovalent Interactions.

ConspectusThe topology of molecular electrostatic potential (MESP), V(r), derived from a reliable quantum chemical method has been used as a powerful tool for the study of intermolecular noncovalent interactions. The MESP topology mapping is achieved by computing both ∇V(r) data and the elements of the Hessian matrix at ∇V(r) = 0, the critical point. MESP minimum (Vmin) as well as MESP at a reaction center, specific to an atom (Vn), have been employed as electronic parameters to interpret the variations in the reactivity (activation/deactivation) of chemical systems with respect to the influence of substituents, ligands, π-conjugation, aromaticity, trans influence, hybridization effects, steric effects, cooperativity, noncovalent interactions, etc. In this Account, several studies involving MESP topology analysis, which yielded interpretations of various noncovalent interactions and also provided new insights in the area of chemical bonding, are highlighted. The existence of lone pairs in molecules is distinctly reflected by the topology features of the MESP minima (Vmin). The Vmin is able to probe lone pairs in molecules, and it has been used as a reliable electronic parameter to assess their σ-donating power. Furthermore, MESP topology analysis can be used to forecast the structure and energetics of lone pair π-complexes. The MESP approach to rationalize lone pair interactions in molecular systems has led to the design of cyclic imines for CO2 capture. The MESP topology analysis of intermolecular complexes revealed a hitherto unknown phenomenon in chemical bonding theory─formation of a covalent bond due to the influence of a noncovalent bond. The MESP-guided approach to intermolecular interactions provided a successful design strategy for the development of CO2 capture systems. The MESP parameters Vmin and MESP at the nucleus, Vn, derived for the molecular systems have been used as powerful measures for the extent of electron donor-acceptor (eDA) interactions in noncovalent complexes. Noncovalent bond formation leads to more negative MESP at the acceptor nucleus (VnA) and less negative MESP at the donor nucleus (VnD). The strong linear relationship observed between ΔΔVn = ΔVnD - ΔVnA and bond energy suggested that MESP data provide a clear evidence of bond formation. Furthermore, MESP topology studies established a cooperativity rule for understanding the donor-acceptor interactive behavior of a dimer D...A with a third molecule. According to this, the electron reorganization in the dimer due to the eDA interaction enhances electron richness at "A", the acceptor, and enhances electron deficiency at "D", the donor. Resultantly, D in D...A is more accepting toward trimer formation, while A in D...A is more donating. MESP topology offers promising design strategies to tune the electron-donating strength in various noncovalent interactions in hydrogen-, dihydrogen-, halogen-, tetrel-, pnicogen-, chalcogen-, and aerogen-bonded complexes and thereby to predict the interactive behavior of molecules. To sum up, MESP topology analysis has become one of the most effective modern techniques for understanding, interpreting, and predicting the intermolecular interactive behavior of molecules.

Реакционная способность арилсульфонилгалогенидов как функция молекулярного электростатического потенциала реакционного центра

To study the reactivity of arylsulfonyl halides, the molecular electrostatic potential (MEP) was considered for the first time as a descriptor. The reaction of hydrolysis of aromatic sulfonyl halides in the medium of mixed acetone-water solvents (according to the literature data of rate constants) was used as a model. The calculation of the structural parameters of the molecules of substituted arylsulfonyl halides was carried out using the ADF2014 software package at the level of the DFT/M06/6-311+G* (PCM) theory. It was found that the magnitude of the MEP on the sulfonyl sulfur atom is very sensitive to changes in the structure of substrates, which makes it possible to determine the change in the ratio between the rate of nucleophilic attack and anionoid abstraction of the leaving group. In particular, using the example of the hydrolysis reaction of substituted thiophenesulfonyl chlorides, it was shown that the acceleration of the reaction is observed with an increase in the donor properties of the substituents and the associated increase in the negative MEP value on the sulfonyl sulfur atom. The antibate character of the dependence of the hydrolysis constant values on the IEP value indicates that not the nucleophilic attack is the rate determining in the interaction of thiophene sulfonyl chlorides and the hydroxyl anion in this sample, but the abstraction of the chloride anion. This reaction has an unstable mechanism, when the ratio between the degree of S-nucleophile bond formation and S-halogen bond cleavage changes. This makes it possible to use MEP as a descriptor of reactivity in the hydrolysis of aryl sulfonyl halides and to elucidate the details of changes in the structure of transition states during the implementation of mechanisms other than pure SN2 mechanism.

Cooperative effects between triel and halogen bonds in complexes of pyridine derivatives: An opposite effect of the nitrogen oxidation on triel and halogen bonds

AbstractAb initio calculations are performed for binary complexes of TrR3···4‐PyX/4‐OPyX and 4‐PyX/4‐OPyX···N‐base (Tr = B, Al; R = H, Cl, Br, I; X = Cl, Br, I; N‐base = HCN, NHCH2, NH3). The halogen bond (XB) is weak but becomes stronger in the HCN(sp) < NH3(sp3) < NHCH2(sp2) pattern. Nitrogen oxidation can enhance the XB a little. The triel bond (TrB) is very strong, with interaction energy ranging from −35 to −58 kcal/mol. The TrB is weaker for the heavier halogen atom in the AlR3 complex, while no such dependence is found in the BR3 complex. The oxygen atom of 4‐OPyX engages in a weaker TrB than the nitrogen atom of 4‐PyX, inconsistent with the negative molecular electrostatic potentials (MEPs) on both atoms. Both TrB and XB are strengthened in TrR3···4‐PyX/4‐PyOX···N‐base. The binding distance of the stronger TrB is shortened to less than that of the weaker XB, which is in contrast to that in BF3···NCH···NCH, where the stronger TrB has a larger shortening in the binding distance. The cooperativity is explained by MEP and charge transfer.

Sigma-holes from iso-molecular electrostatic potential surfaces.

Visualization of the halobenzene σ-hole region of molecules (PhX, X = Cl, Br, I) was conducted to investigate the nature of the σ-hole present between covalently bonded elements of groups IVB-VIIB (known as halogen bonding for group VIIB) and corresponding negative sites, such as Lewis base lone electron pairs, π-electrons, or anions. The σ-hole consists of a region of poor electron density and often relatively positive electrostatic potential surrounding the outermost portion of the halogen atom along the A-X bond axis. In this work, molecular electrostatic potential (MEP) isosurfaces for PhX obtained from ab initio calculations are examined to determine the σ-hole in 3D, showing the surfaces of corresponding positive and negative regions. Surfaces were mapped for isopotentials of PhX molecules as low as 0.003V and scaled up by factors of 10 up to 3V. The σ-hole is revealed as a positive region exposed underneath a predominantly negative MEP isosurface. As isopotential values move away from zero, this hole grows in radius; conversely, its presence completely fades as potential approaches zero with increasing distance from the molecule. This technique can also be used to compare behaviors of neutral molecules and their ionic counterparts like the case of neutral PF6 (not observed experimentally) and the hexafluorophosphate anion, PF6-, a typical counter-ion in commercial Li-ion batteries. The pnictogen halide PF5 features similar MEP trends as the neutral PF6, which features reactive sites, shown as negative potential caps, at specific points in the molecule, similar to those of PF5. The portrayal of MEP behavior in iso-surfaces at specific and practical values of chemical interest is crucial when defining lump parameter sets for Coulombic force fields for molecular dynamics simulations to be used in systems that go from biological macromolecules to crystal engineering to devices to final products. Active chemical sites can be described by the MEP function, V(r), more proficiently than just wavefunctions or electron densities that intrinsically contain the same information, and this is fully enhanced when color-coding electron densities on isopotential surfaces are shown. Graphical abstract The hidden features of orbital holes depicted by iso-potentials.

Comparison of Various Means of Evaluating Molecular Electrostatic Potentials for Noncovalent Interactions.

The various heterodimers formed by a series of Lewis acids with NH3 as Lewis base are identified. Lewis acids include those that can form chalcogen (HSF and HSBr), pnicogen (H2 PF and H2 PBr), and tetrel (H3 SiF and H3 SiBr) bonds, as well as H-bonds and halogen bonds. The molecular electrostatic potential (MEP) of each Lewis acid is considered in a number of ways. Pictorial versions show broad regions of positive and negative MEP, on surfaces that vary with respect to either the value of the chosen isopotential, or their distance from the nuclei. Specific points are identified where the MEP reaches a maximum on a particular isodensity surface (Vs,max ). The locations and values of Vs,max were evaluated on different isodensity surfaces, and compared to the stabilities of the various equilibrium geometries. As the chosen isodensity is decreased, and the MEP maxima drift away from the molecule, some points maintain their angular positions with respect to the molecule, whereas others undergo a reorientation. The lowering isodensity also causes some of the maxima to disappear. In general, there is a fairly good correlation between the energetic ordering of the equilibrium structures and the values of Vs,max . A number of possible Lewis acid sites on the heteroaromatic imidazole ring were also considered and presents some cautions about application of Vs,max as the principal criterion for predicting equilibrium geometries. © 2017 Wiley Periodicals, Inc.

Trifluoromethyl: An Amphiphilic Noncovalent Bonding Partner.

The traditional "Fδ- " picture of fluorine suggests that it can only interact with electrophilic centers such as backbone-carbonyl carbon atoms or hydrogen-bond donors in proteins. We show that this view, which neglects polarization, is incomplete and the trifluoromethyl groups can act both as electrophiles and nucleophiles to form noncovalent interactions. The underlying polarization mechanism is based on the anomeric effect and is only fully operative if the geometry is allowed to relax. MP2/aug-cc-pVDZ calculations on model systems demonstrate the effect of the unusual group polarizability of trifluoromethyl. A survey of the Protein Databank reveals more than 600 weak interactions involving a trifluorotoluene moiety. The unique combination of the anomeric effect and the group-polarization process associated with it in CF3 allows its most negative molecular electrostatic potential (MEP) on the surface in contact with a nucleophile to become zero, so that the area of positive MEP on the backside of the carbon atom becomes dominant. However, the reverse polarization is also facile, so that CF3 can also act as an H-bond acceptor for cations such as the guanidinium group of arginine.

An ab initio study on tunability of σ-hole interactions in XHS:PH2Y and XH2P:SHY complexes (X = F, Cl, Br; Y = H, OH, OCH3, CH3, C2H5, and NH2).

Quantum chemical calculations are performed to investigate the tunability of σ-hole interactions in chalcogen-bonded XHS:PH2Y and pnicogen-bonded XH2P:SHY complexes, where X = F, Cl, Br and Y = H, OH, OCH3, CH3, C2H5, NH2. The formation of these binary complexes can be understood in terms of molecular electrostatic potentials (MEPs), considering the P and S atoms as an electron acceptor or an electron donor in the chalcogen and pnicogen bonds. The strength of the XHS:PH2Y and XH2P:SHY complexes for a given Y increases as follows: X = Br < Cl < F. In addition, an acceptable linear relationship is found between the interaction energies and the magnitudes of the product of most positive and negative MEPs. This finding along with the electron density difference maps provides a clear picture of the electrostatic nature of the interactions in the XHS:PH2Y and XH2P:SHY complexes. The calculated spin-spin coupling constants across the chalcogen bond interactions in the XHS:PH2Y complexes display a quadratic dependence with the P···S binding distance.

A DFT study of substituent effects in corannulene dimers

Corannulene dimers made up of corannulene monomers with different curvature and substituents were studied using M06-2X, B97D and ωB97XD functionals and 6-31+G* basis set. Corannulene molecules were substituted with five alternating Br, Cl, CH(3), C(2)H or CN units. Geometric results showed that substituents gave rise to small changes in the curvature of corannulene bowls. So, there was not a clear relationship between the curvature of bowls and the changes on interaction energy generated by addition of substituents in the bowl. Electron withdrawing substituents gave rise to a more positive molecular electrostatic potential (MEP) of the bowl, which was able to get a strong interaction with the negative MEP at the surface of a fullerene. Substitution with CN caused the largest effect, giving rise to the most positive MEP and to a large interaction energy of -24.64 kcal mol(-1), at the ωB97XD/6-31+G* level. Dispersive effects must be taken into account to explain the catching ability of the different substituted corannulenes. For unsubstituted dimers, calculations with DFT-D methods employing ωB97XD and B97D functionals led to similar results to those previously reported at the SCS-MP2/cc-pVTZ level for corannulene dimers (A. Sygula and S. Saebø, Int. J. Quant. Chem., 2009, 109, 65). In particular, the ωB97XD functional led to a difference of only 0.35 kcal mol(-1), regarding MP2 interaction energy for corannulene dimers. On the other hand, the M06-2X functional showed a general considerable underestimation of interaction energies. This functional worked quite well to study trends, but not to obtain absolute interaction energies.

Intramolecular S···O chalcogen bond in thioindirubin

Results of X-ray diffraction study and quantum-chemical calculations revealed that molecular conformation of thioindirubin molecule creates suitable conditions for formation of intramolecular C–H···O and S···O interactions. Analysis of molecular electrostatic potential (MEP) demonstrates existence of two areas of positive MEP (σ-holes) in the outermost part of the sulfur atom on the continuation of the lines of the C–S bonds. One of these σ-holes is oriented toward region of negative MEP around the oxygen atom of carbonyl group. Such situation corresponds to formation of σ-hole or chalcogen bond. Existence of both types of bonding interactions is confirmed by topological analysis of electron density distribution using “Atoms in Molecules” (AIM) theory. Energies of the C–H···O hydrogen bond and the S···O σ-hole bond derived from AIM and NBO theories are very close.

Metodologia AGOA: a modelagem de clusters de hidratação no complexo aziridina···ácido fluorídrico

We present a theoretical study of solvent effect on C2H5N···HF hydrogen-bonded complex through the application of the AGOA methodology. By using the TIP4P model to orientate the configuration of water molecules, the hydration clusters generated by AGOA were obtained through the analysis of the molecular electrostatic potential (MEP) of solute (C2H5N···HF). Thereby, it was calculated the hydration energies on positive and negative MEP fields, which are maxima (PEMmax) and minima (PEMmin) when represent the -CH2- methylene groups and hydrofluoric acid, respectively. By taking into account the higher and lower hydration energy values of -370.6 kJ mol-1 and -74.3 kJ mol-1 for PEMmax and PEMmin of the C2H5N···HF, our analysis shows that these results corroborate the open ring reaction of aziridine, in which the preferential attack of water molecules occurs at the methylene groups of this heterocyclic.

Molecular basis of the low activity of antitumor anthracenediones, mitoxantrone and ametantrone, in oxygen radical generation catalyzed by NADH dehydrogenase. Enzymatic and molecular modelling studies

Synthetic antitumor anthracenedione drugs, in contrast to anthracycline antibiotics, are ineffective in free radical formation in NADH dehydrogenase system. Our results have indicated that neither the reduction potential nor the side chain conformation and the energies of border orbitals (HOMO and LUMO) determine the ability of anthracenediones to stimulate reactive oxygen species formation in NADH dehydrogenase system. It was shown that the distribution of the molecular electrostatic potential (MEP), around the quinone system was crucial for this ability. We have found for non-stimulating anthracenediones that the clouds of positive MEP cover the quinone carbon atoms while for agents effective in stimulating reactive oxygen species formation the clouds of negative MEP cover continuously the aromatic core together with the quinone system.

Molecular electrostatic potential maps of the anti-cancer drugs daunomycin and adriamycin: an ab initio theoretical study

Molecular geometries of the anti-cancer drug molecules adriamycin and daunomycin were optimized using the restricted Hartree–Fock procedure and the 6-31G and 6-31G* basis sets. Molecular electrostatic potentials (MEP) were obtained on the van der Waals surfaces of the molecules using the MEP-derived CHelpG point charges. MEP minima and MEP surfaces corresponding to chosen MEP values were obtained using the continuous electron density distributions at the SCF level. Hydrogen bonding interactions involving the drug molecules, DNA and the surrounding environment suggested in experimental studies earlier are mostly supported by the present MEP values. However, this study also reveals additional useful information in the sense that the calculated MEP values near the different atoms vary over a wide range indicating that the hydrogen bond strengths involving them would also vary appreciably. Occurrence of a strong binding of a Na + ion to both O 4 and O 5 is indicated by the present MEP patterns. Further, the role of the binding of an oxygen atom that is present in adriamycin but not in daunomycin and is associated with a large negative MEP value with DNA appears to be very important due to which the former drug is more effective as an anti-cancer agent than the latter.

Solution structure of a guanine-N7-linked complex of the mitomycin C metabolite 2,7-diaminomitosene and DNA. Basis of sequence selectivity.

2,7-Diaminomitosene (2,7-DAM), the major metabolite of the antitumor antibiotic mitomycin C, forms DNA adducts in tumor cells. 2,7-DAM was reacted with the deoxyoligonucleotide d(GTGGTATACCAC) under reductive alkylation conditions. The resulting DNA adduct was characterized as d(G-T-G-[M]G-T-A-T-A-C-C-A-C) (5), where [M]G stands for a covalently modified guanine, linked at its N7-position to C10 of the mitosene. The adducted oligonucleotide complements with itself, retaining 2-fold symmetry in the 2:1 drug-duplex complex, and provides well-resolved NMR spectra, amenable for structure determination. Adduction at the N7-position of G4 ([M]G, 4) is characterized by a downfield shift of the G4(H8) proton and separate resonances for G4(NH(2)) protons. We assigned the exchangeable and nonexchangeable proton resonances of the mitosene and the deoxyoligonucleotide in adduct duplex 5 and identified intermolecular proton-proton NOEs necessary for structural characterization. Molecular dynamics computations guided by 126 intramolecular and 48 intermolecular distance restraints were performed to define the solution structure of the 2,7-DAM-DNA complex 5. A total of 12 structures were computed which exhibited pairwise rmsd values in the 0.54-1.42 A range. The 2,7-DAM molecule is anchored in the major groove of DNA by its C10 covalently linked to G4(N7) and is oriented 3' to the adducted guanine. The presence of 2,7-DAM in the major groove does not alter the overall B-DNA helical structure. Alignment in the major groove is a novel feature of the complexation of 2,7-DAM with DNA; other known major groove alkylators such as aflatoxin, possessing aromatic structural elements, form intercalated complexes. Thermal stability properties of the 2,7-DAM-DNA complex 5 were characteristic of nonintercalating guanine-N7 alkylating agents. Marked sequence selectivity of the alkylation by 2,7-DAM was observed, using a series of oligonucleotides incorporating variations of the 5'-TGGN sequence as substrates. The selectivity correlated with the sequence specificity of the negative molecular electrostatic potential of the major groove, suggesting that the alkylation selectivity of 2,7-DAM is determined by sequence-specific variation of the reactivity of the DNA. The unusual, major groove-aligned structure of the adduct 5 may account for the low cytotoxicity of 2,7-DAM.

Modeling of Supramolecular Properties of Molecular Tweezers, Clips, and Bowls

The electrostatic potential surface (EPS) is calculated for molecular tweezers, clips, and bowls at different levels of theory (semiempirical AM1, ab initio HF/6-31G*, and density functional theory pBP/DN**). According to these calculations, the molecular electrostatic potential (MEP) on the concave side of the molecular tweezers and clips is suprisingly negative for hydrocarbons. This finding seems to be a general phenomenon in nonconjugated π-electron systems with concave-convex topology and it explains the receptor properties of the molecular tweezers and clips. Analogous calculations performed for the conjugated aromatic molecular bowls show different results. The DFT calculations predict that in these systems the more negative MEP lies on the concave side similar to the findings for the nonconjugated molecular tweezer- and clip-systems, whereas the AM1 calculation leads to the opposite result that the MEP is more negative on convex side of the bowl-systems.

Molecular modeling study of diltiazem mimics at L-type calcium channels.

A theoretical study was performed to generate a pharmacophore model for chemically diverse structures that specifically interact with the diltiazem binding site of L-type calcium channels. Via molecular mechanics and quantum chemical methods solvation energies, logP values, conformational and electronic features of classical 1,5-benzothiazepin-4(5H)-one (BTZ, e.g., diltiazem), 1-benzazepin-2-one (BZ), pyrrolo[2,1-d][1,5]benzothiazepine, pyrrolo[2,1-c][1,4]benzothiazine, and benzobicyclo[2.2.2]octyl amines derivatives were determined. Furthermore, the molecular electrostatic potentials (MEPs) and common interaction fields derived from use of the GRID programme were compared. This yielded a pharmacophore model with three crucial pharmacophoric characteristics, (1) two aromatic ring systems in a distance of about 6.7 A, (2) a basic side chain with pKa in the physiological range, and (3) a 4'-methoxy moiety. In addition, a strong negative MEP in 4-position (carbonyl oxygen) and hydrophobic electron-rich features in the position equivalent to the sulphur atom of BTZ derivatives were explored to be favourable for receptor binding and calcium antagonistic effect. Moreover, the stabilizing effect of substituents in 3-position of BZs on the bioactive "M" twist-boat conformation of the heptagonal ring could be demonstrated by molecular dynamics simulations. Based on these molecular descriptors, the quinazolinone derivative MCI-176 is predicted to be a potential ligand of the diltiazem binding site.

Comparison of electrostatic similarity approaches applied to a series of ketanserin analogues with 5-HT2A antagonistic activity

Similarities between the molecular electrostatic potential (MEP) distributions of a series of analogues of ketanserin were studied using the MEPSIM package with the aim of correlating MEP patterns with the binding affinities for the 5-HT2A receptor. This study was also used to assess different approaches that can be used in this kind of similarity studies. The best correlation between MEP distributions and biological activities was found when only negative electrostatic potentials were taken into account, while the consideration of the whole MEP distribution produced a classification of the compounds than was mainly steric and not related with their biological activities. The two structural features of the considered molecules that generated negative MEP zones and consequently that could be related with their recognition by the 5-HT2A receptor, were the lone pairs of a carbonyl oxygen and the π-system of an aromatic ring.

Structure-Activity Relationship for Some 2′,3′-Dideoxynucleoside Anti-HIV Drugs Using Molecular Electrostatic Potential Mapping

Molecular electrostatic potential(MEP) maps of azido thymidine (AZT), some of its analogs and derivatives and certain other 2′,3′-dideoxy nucleosides having different anti-HIV activities have been studied. The optimised hybridization displacement charges (HDC) combined with MNDO Lowdin charges, continuosly distributed in three dimension spherically symmetrically as a Slater cloud at each site were used to compute the MEP maps. The negative MEP region near the O5′ sites of these molecules appears to be of primary importance from the point of view of their anti-HIV activity. The roles of the azido group in AZT and fluorine atoms substituted at different positions in the sugar moiety have been evaluated. The azido group in AZT behaves as a strongly electronegative group.

Derivation of fused-sphere molecular surfaces from properties of the electrostatic potential distribution

The distribution of molecular electrostatic potential (MEP) on a surface is a common model used to describe simultaneously steric properties (e.g., size, shape) and reactive properties (e.g., electro- and nucleophilic positions) of a molecule. In this work, we analyze some relations between these two properties. In particular, we explore the possible definition of an optimum fused-sphere molecular surface from properties of the MEP distribution. With this goal, we study how several statistical descriptors of the two-dimensional MEP distribution change upon shrinking or enlarging a van der Waals surface. We find that some of the descriptors exhibit critical points in terms of a scaling factor. We use this property to define effective atomic radii. In particular, we find that a reasonable molecular envelope is defined as the surface having the lowest (i.e., most negative) average negative MEP, with the largest possible dispersion about the mean. We discuss the resulting atomic radii and compare them with others in the literature derived from only steric considerations. The present results expand the scope of fused-sphere surfaces for modeling microscopic or structural molecular properties. © 1996 by John Wiley & Sons, Inc.

An electrostatic investigation: how polar are ionic surfactant hydrocarbon tails?

It is shown that a negative molecular electrostatic potential (MESP) surface completely surrounds all the atoms in any surfactant anion; further, negative MESP at the hydrocarbon ends of n-dodecanoate and n-decylsulfate is almost six times that for the n-dodecane and n-decane molecules respectively; this negative MESP build-up from the polar head group through the molecule up to the end of the hydrocarbon tail leads to finite, decreasing hydration probability along the chain.

A predictive substrate model for rat glutathione S-transferase 4-4.

Molecular modeling techniques have been used to derive a substrate model for class mu rat glutathione S-transferase 4-4 (GST 4-4). Information on regio- and stereoselective product formation of 20 substrates covering three chemically and structurally different classes was used to construct a substrate model containing three interaction sites responsible for Lewis acid--Lewis base interactions (IS1, IS2, and IS3), as well as a region responsible for aromatic interactions (IS4). Experimental data suggest that the first protein interaction site (pIS1, interacting with IS1) corresponds with Tyr115, while the other protein interaction sites (pIS2 and pIS3) probably correspond with other Lewis acidic amino acids. All substrates exhibited positive molecular electrostatic potentials (MEPs) near the site of conjugation with glutathione (GSH), as well as negative MEP values near the position of groups with Lewis base properties (IS1, IS2, or IS3), which interact with pIS1, pIS2, or pIS3, respectively. Obviously, complementarity between the MEPs of substrates and protein in specific regions is important. The substrate specificity and stereoselectivity of GST 4-4 are most likely determined by pIS1 and the distance between the site of GSH attack and Lewis base atoms in the substrates which interact with either pIS2, pIS3, or a combination of these sites. Interaction between aromatic regions in the substrate with aromatic amino acids in the protein further stabilizes the substrate in the active site. The predictive value of the model has been evaluated by rationalizing the conjugation to GSH of 11 substrates of GST 4-4 (representing 3 classes of compounds) which were not used to construct the model. All known metabolites of these substrates are explained with the model. As the computer-aided predictions appear to correlate well with experimental results, the presented substrate model may be useful to identify new potential GST 4-4 substrates.