Showing papers on "Conformational isomerism published in 1995"

Poling: Promoting conformational variation

Abstract: This article introduces several methods of assessing the extent to which a collection of conformations represents or covers conformational space. It also describes poling: a novel technique for promoting conformational variation that can be applied to any method of conformational analysis that locally minimizes a penalty or energy function. The function being minimized is modified to force similar conformers away from each other. The method is independent of the origin of the initial conformers and of the particular minimization method used. It is found that, with the modification of the penalty function, clustering of the resulting conformers is generally unnecessary because the conformers are forced to be dissimilar. The functional form of the poling function is presented, and the merits are discussed with reference to (1) efficacy at promoting variation and (2) perturbation of the unmodified function. Results will be presented using conformers obtained from distance geometry with and without poling. It will be shown that the addition of poling eliminates much redundancy in conformer generation and improves the coverage of the conformational space. © 1995 by John Wiley & Sons, Inc.

Side-chain conformational entropy in protein folding

Abstract: An important, but often neglected, contribution to the thermodynamics of protein folding is the loss of entropy that results from restricting the number of accessible side-chain conformers in the native structure. Conformational entropy changes can be found by comparing the number of accessible rotamers in the unfolded and folded states, or by estimating fusion entropies. Comparison of several sets of results using different techniques shows that the mean conformational free energy change (T delta S) is 1 kcal.mol-1 per side chain or 0.5 kcal.mol-1 per bond. Changes in vibrational entropy appear to be negligible compared to the entropy change resulting from the loss of accessible rotamers. Side-chain entropies can help rationalize alpha-helix propensities, predict protein/inhibitor complex structures, and account for the distribution of side chains on the protein surface or interior.

Conformational Changes in Diethylene Glycol Dimethyl Ether and Poly(ethylene oxide) Induced by Lithium Ion Complexation

Abstract: Conformational changes in diethylene glycol dimethyl ether (diglyme) and high molecular weight poly(ethylene oxide) induced by complexation with lithium trifluoromethanesulfonate (LiCF 3 SO 3 ) have been investigated using Raman scattering and infrared transmission spectroscopy. In both the diglyme and polymer complex new bands were observed in spectral regions involving a significant amount of CH 2 bending motion. These bands are attributed to a conformation which is not energetically favored in the pure polymer or oligomer but which is stabilized through interactions of the cation with the polyether oxygen atoms. The structure of the new conformer is discussed.

The use of the AMBER force field in conformational analysis of carbohydrate molecules: determination of the solution conformation of methyl alpha-lactoside by NMR spectroscopy, assisted by molecular mechanics and dynamics calculations.

Abstract: The solution conformation of methyl α-lactoside has been studied through nmr spectroscopy and molecular mechanics calculations using the assisted model building with energy refinement (AMBER) force field. The nmr data have included nuclear Overhauser effect (NOE) measurements hot It in the laboratory and rotating frames, longitudinal relaxation times, and homonuclear and heteronuclear coupling constants. The steady-state and transient NOEs have been interpreted in terms of an ensemble average distribution of conformers, making use of the complete relaxation matrix approach. The molecular mechanics calculations have been performed at two dielectric constants [e = 1 * r and 80 Debyes (D)] in an exhaustive way, and have been complemented with specific calculations at intermediate e values. Relaxed energy maps and adiabatic surfaces have been generated for the different dielectric constants. The probability distribution of conformers has been estimated from these steric energy maps. Molecular dynamics simulations in vacuo have also been performed. The experimental results indicate that the β(1 4)-glycosidic linkage shows some fluctuations among three low energy regions, although spends ca. 85% of its lime in the region close to the global minimum. It is shown that the over estimation of the electrostatic contributions in AMBER is responsible for the failure of this force field to explain the experimental results when Used at low dielectric constant (e 40 D. Different conditions have been tested to perform temperature constant molecular dynamics simulations in vacuo, which have indicated that, when used without explicit solvent, this force field should only be employed in a qualitatively way when analyzing dynamical properties of oligosaccharides. © 1995 John Wiley & Sons, Inc.

Do band 3 protein conformational changes mediate shape changes of human erythrocytes

Abstract: The bilayer-couple model predicts a reversible membrane crenation for an increasing ratio of external to internal monolayer area. This was comprehensively proven. However, individual erythrocytes may undergo dramatic shape changes within seconds when the suspension medium is changed. In contrast, under physiological conditions with no addition of membrane active compounds, active phospholipid translocation and passive flip-flops are comparatively slow. We propose that conformational changes of the anion-exchange protein, band 3, may rapidly alter the monolayer area ratio. Band 3 occupies about 10% of the total membrane area of human erythrocytes. Under physiological conditions, its conformers are asymmetrically distributed with about 90% of the transport sites facing the cytoplasm. This distribution is altered when external conformations are recruited by changing the transmembranous CI− gradient, the external pH, or by the application of inhibitors. In experiments, recruitment by low ionic strength caused...

Rotational isomerism in acrylic acid. A combined matrix-isolated IR, Raman and ab initio molecular orbital study

Abstract: The results of a combined vibrational and structural study of the acrylic acid monomer undertaken by matrix-isolated low-temperature IR spectroscopy and ab initio SCF-HF and MP2 MO calculations are presented. In addition, both Raman and IR spectra of liquid acrylic acid and the Raman spectrum of the crystal are also reported and interpreted. It is shown that in both argon and krypton matrices acrylic acid monomer exists as a mixture of two conformers of similar energies, differing by the relative orientation of the CC—CO axis. Upon irradiation at λ= 243 nm by a xenon lamp, the s-cis form (CC—CO dihedral angle equal to 0 °), corresponding to the conformational ground state, converts to the s-trans form (CC—CO dihedral angle equal to 180 °). In the liquid phase, dimeric structures strongly predominate, but the existence in this phase of the two conformational states referred to above can also be inferred from the corresponding vibrational spectra. In turn, in the crystal only the thermodynamically most stable form (s-cis) exists. Results of ab initio SCF-HF and MP2 molecular orbital (MO) calculations, in particular optimised geometries, relative stabilities, dipole moments and harmonic force fields, for the relevant conformational states of acrylic acid are also presented and the conformational dependence of some relevant structural parameters is used to characterise the most important intramolecular interactions present in the studied conformers. Finally, the calculated vibrational spectra and both the results of a normal-mode analysis based on the theoretical harmonic force fields and of IR intensity studies based on the charge–charge flux–overlap (CCFO) model were used to help interpret the experimental vibrational data, enabling a detailed assignment of the acrylic acid spectra obtained in the different conditions considered.

Conformational analysis and flexibility of carbohydrates using the CICADA approach with MM3

Abstract: The potential energy hypersurfaces (PES) of several carbohydrate molecules were studied with a new algorithm for conformational searches, CICADA (Channels in Conformational Space Analyzed by Driver Approach) interfaced with the molecular mechanics program MM3(92). The method requires (1) one or a few low-energy conformations as starting points; and (2) designation of the torsion angles important for understanding the conformational behavior of the molecule. The PES is explored by driving separately each selected torsion angle (in both directions) with a concomitant full-geometry optimization at each increment (except for the driven angle). When a minimum has been detected, the molecule is freely optimized, and the minima so detected are then stored if not encountered previously. The new minima serve as starting structures for further explorations. The results from CICADA permit prediction of relative and absolute flexibility and conformational softness for both the entire molecule as well as for individual group rotations and local minima. The carbohydrates analyzed were Me-α-D-glucopyranoside, β-D-GlcNAc(1-2)α-D-Man, and α-D-GalNAc(1-3)[α-L-Fuc(1-2)]Gal-O-Me. All the low-energy conformers along with the transition states and flexibilities features were characterized. CICADA found all minima and low-energy conversion pathways for the disaccharide that were found by a traditional grid search. In contrast to the grid search method, CICADA concentrates mostly on the exploration of the low-energy regions of the PES, thereby saving a significant amount of computational time. The performance of the method opens new routes for exploring conformational space of larger molecules, such as oligosaccharides. © 1995 by John Wiley & Sons, Inc.

The molten helix : effects of solvation on the alpha - to 310-helical transition

Abstract: Free energy surfaces, or potentials of mean force, for the alpha- to 3(10)-helical conformational transition in polypeptides have been calculated in several solvents of different dielectric. The alpha- to 3(10)-helical transition has been suggested as potentially important in various biological processes, including protein folding, formation of voltage-gated ion channels, kinetics of substrate binding in proteins, and signal transduction mechanisms. This study investigates the thermodynamics of the alpha- to 3(10)-helical transition of a model peptide, the capped decamer of alpha-methylalanine, in order to assess the plausibility of this transition in the mechanisms of such biological processes. The free energy surfaces indicate that in each environment studied the alpha-helical conformation is the more stable of the two for the decapeptide, The thermodynamic data suggest that the alpha-helix is energetically stabilized and the 3(10)-helix is entropically favored. The inclusion of dichloromethane, acetonitrile, or water results in approximately 7 kcal/mol of relative conformational energy (favoring the alpha-helix) and 3 kcal/mol of relative conformational entropy (favoring the 3(10)-helix) in comparison to the gas phase. In polar environments, the alpha-helix is stabilized by its more favorable salute-solvent electrostatic interactions, and solute-solute steric interactions. In addition, it was concluded that in polar solvents, especially water, it is possible for the peptide to reduce some of the inherent strain of the 3(10)-helix by widening psi, the resulting weaker intrasolute hydrogen bonds being compensated for by increased-hydrogen bonding to the solvent. Lower polarity environments are associated with a marginally increased relative stability of the 3(10)-helix, which we suggest is largely due to the additional intrahelical hydrogen bond of this conformation. The data suggest that, in environments such as membranes, the interior of proteins or crystals, the complete transition from an ct-helix to a 3(10)-helix for this decapeptide would require less than 6 kcal/mol in free energy. Switching conformations for individual residues is much more facile, and shorter 3(10)-helices may actually be energetically favored, at least, in nonpolar environments. This study primarily estimates the backbone contribution to the helical transition; side chain interactions would be expected to play a significant role in stabilizing one conformer relative to the other. It is, therefore, quite feasible that the alpha- to 3(10)-helical transition could provide a possible mechanism for many biological processes. While there are many factors, such as helix length and side chain packing, that contribute to the selection of either the alpha- or the 3(10)-helical conformation or a mixture of the two, this study focuses primarily on one of these effects, that of the polarity of the environment.

Photoreactions of the photointermediates of bacteriorhodopsin

Abstract: The photochemical reactions of the intermediates of the photochemical cycle of bacteriorhodopsin (bR) are reviewed. These reactions constitute photochemical control of the cycle and provide an independent approach for the investigation of the mechanism of light energy transduction in the purple membrane. The absorption of a light quantum by the K, L, or M intermediates converts them back to bR. These transformations interrupt the photocycle so that no proton transfer occurs after absorption of the second quantum. The action of blue light on the M intermediate causes structural changes of the chromophore, as a result of which the Schiff base is reprotonated from Asp-85, not from Asp-96 as in the usual thermal transition of M. The photoreactions of the L, M, N, and O intermediates lead to the formation of new photoproducts. Studies of the photoconversion of the intermediates can serve as an additional source of information on the nature of photoprocesses in bR: they reveal several conformers of K and bR at 90 K, different M states, two N intermediates, and provide direct evidence for the existence of a thermal back reaction from N to M. The study of the photoreactions of the J, K, L, M, N, and O intermediates is a promising method for elucidating the structures and roles of these states. Reversible photoconversions of bR and its photointermediates provide a basis for potential applications of bR in optical registration of information.

Acetylketene : conformational isomerism and photochemistry matrix isolation infrared and ab initio studies

Abstract: The s-Z and s-E conformers of acetylketene (5) were generated by flash vacuum pyrolysis (FVP) and matrix photolysis of precursors 1-4. Both conformers were characterized by low-temperature IR spectroscopy in argon, xenon, and nitrogen matrices. The observed frequencies and intensities are in excellent agrement with ab initio calculations at the MP2/6-31G* level. UV irradiation of s-Z/s-E-5 in nitrogen or xenon matrices allows the clean interconversion of conformers. Prolonged UV irradiation resulted in decarbonylation and formation of methylketene (7). However, the photolysis of argon matrix isolated 5 produced a new set of bands in the IR spectrum very close to the s-Z/s-E absorptions. Annealing of the matrix to 35 K removed these bands. This unusual phenomenon was shown to be due to a photochemically induced matrix site effect. Consistent with experimental observations, high-level calculations (QCISD(T)/6-311+G(2d,p)+ZPVE) predict that the s-Z and s-E conformers have virtually identical energies.

Molecular design of novel liquid crystalline polymers with complex architecture: Macrocyclics and dendrimers

Abstract: This paper discusses recent results from our laboratory on the molecular design of two novel classes of liquid crystals with complex architecture, ie, supramolecular quasi-rigid-rods generated from collapsed macrocyclics and dendrimers based on flexible AB2 monomers which exhibit conformational isomerism

Gamma irradiation of 2'-deoxyadenosine in oxygen-free aqueous solutions: identification and conformational features of formamidopyrimidine nucleoside derivatives.

Abstract: The two major radiation-induced decomposition products of 2'-deoxyadenosine in oxygen-free aqueous solution have been isolated by reverse-phase HPLC. The 1H and 13C NMR features of the two modified nucleosides obtained in DMSO-d6 are indicative of a similar formamidopyrimidine structure for the base residue (the ring-opened form of a C-8 hydroxylated purine). Interestingly, the sugar moiety exhibits a pyranose configuration, the two nucleosides being a pair of alpha and beta anomers. One-bond and long-range 1H-13C 2D NMR experiments have allowed the complete assignment of the carbon atoms. Confirmation of the base structure was obtained by 1H-15N scalar-correlated 2D NMR experiments. Attempts were made to characterize the expected furanose form of the initially generated formamidopyrimidine derivative. In this respect, isomerization reaction of the sugar moiety of the latter compound takes place rapidly after gamma-irradiation as inferred from 1H NMR analysis. The conformational study of the sugar moiety of the two pyranose anomers was inferred from detailed 600.13 MHz 1H NMR analysis in D2O. The alpha anomer exhibits a predominant 1C4 conformation whereas the beta anomer adopts preferentially a 4C1 conformation. In addition, the dynamic study of the restricted rotation of the formamido bond has revealed a 1/5 ratio in favor of the s-cis rotamer for both nucleosides. The energy barrier at coalescence was determined to be delta G# = 75.5 kJ.mol-1 (Tc = 370 K).

Studies of the Bound Conformations of Methyl α-Lactoside and Methyl β-Allolactoside to Ricin B Chain Using Transferred NOE Experiments in the Laboratory and Rotating Frames, Assisted by Molecular Mechanics and Dynamics Calculations

Abstract: The conformation in solution of methyl β-galactopyranosyl-(14)-α-glucopyranoside (methyl α-lacto-side) and methyl β-galactopyranosyl-(16)-β-glucopyranoside (methyl β-allolactoside) has been studied through NMR spectroscopy and molecular mechanics calculations. NOE measurements both in the laboratory and rotating frames, have been interpreted in terms of an ensemble average distribution of conformers. Molecular mechanics calculations have been performed to estimate the probability distribution of conformers from the steric energy maps. The experimental results indicate that methyl α-lactoside spends about 90% of its time in a broad low-energy region close to the global minimum, while methyl β-allolactoside presents much higher flexibility. The conformational changes that occur when both disaccharides are bound to the ricin B chain in aqueous solution have been studied using transferred NOE experiments at several protein/ligand ratios. The observed data indicate that the protein causes a conformational variation in the torsion angles of methyl α-lactoside changing towards smaller angle values (ф/Ψ≈–20/–20), although the recognized conformer is still within the lowest energy region. In particular, the torsional changes separate Gal HI from Glc H3 and Glc H6 protons, with a noticeable decrease in the intensities of the corresponding NOE cross-peaks, which were clearly observed for the free disaccharide. On the other hand, different conformations around the ф, Ψ, and ω glycosidic bonds of methyl β-allolactoside are recognized by the lectin. In fact, for the methyl-β-allolactoside–ricin-B complex, only the NOESY cross-peaks corresponding to the protons of the galactose residue are negative, as expected for a molecule in the slow motion regime. In contrast, the corresponding cross peaks for the glucose residue were about zero, as expected for a molecule whose motion is practically independent of the protein. However, for the methyl-α-lactoside-ricin-B complex, all the NOESY cross-peaks for both the galactose and glucose moieties were clearly negative. From the NMR experimental point of view, it is demonstrated that the comparison of longitudinal and transversal transferred NOEs allows one to clearly differentiate direct enhancements from spin diffussion effects, which are of major concern when analysing NOE spectra of macromolecules. Finally, molecular modelling of both disaccharides in the binding site strongly suggests that, for methyl α-lactoside, apart from the expected contacts between the galactose moiety and different amino acid residues, there are also van der Waals' contacts between the protein and the remote glucose moiety, as previously deduced from binding studies using modified lactoside derivatives [Solis, D., Fernandez, P., Diaz-Maurino, T., Jimenez-Barbero, J. & Martin-Lomas, M. (1993) Eur. J. Biochem. 214, 677–683]. This result is in contrast with the X-ray crystallographic analysis of the ricin-B–lactose and ricin-B–galactose-containing diantennary hexasaccharide complexes [Rutenber, E. & Robertus, J. D. (1991) Proteins 10, 260–269]. On the other hand, for methyl β-allolactoside, the experimental data and the modelling studies demonstrate that only the galactose moiety is bound by the lectin and, therefore, the conformation around the glycosidic angles can be probably described by a distribution similar to that existing in free solution.

Ylidyl-dihalogenphosphane – Strukturbilder einer sich anbahnenden Dissoziation

Abstract: Ylidyl-dihalophosphanes Provide Structural Snapshots on Their Way to Dissociation The reaction of phosphonium ylides with phosphorus trihalides has been studied for the synthesis of ylidyl-dihalophos-phanes (= dihalophosphanyl ylides) Ph3PCRPX23, X = Cl, and 9, X = Br. Compounds 3, R = aryl, are readily prepared from the phosphonium bromides [Ph3PCH2R]Br, compounds 3, R = alkyl, SiMe3 or PCl2, and 9 are obtained from silylylides Ph3PCRSiMe3, compound 3, R = PPh3+ results from the addition of PCl3 to the hexaphenylcarbodiphosphorane. A (β-morpholinovinyl)dichlorophosphane 12 has also been prepared. Ylides 3 are oxidized by sulfur and selenium and are converted to ylidyl-chlorophosphenium (= chloro-phosphaalkenyl-phosphonium) salts [Ph3PCRPCl]AlCl410. In the 31P-NMR spectra of 3 and 9 the geminal coupling 2JPP indicates the phosphorus lone pair to be synperiplanar to the phosphonio group. In one case the P(III)C rotation barrier has been estimated from VT-31P-NMR spectra. By X-ray crystallography the structures of 3, R = Me, 2,6-Cl2C6H4, 4-NO2C6H5, PCl2, of 9, R = Me (two molecules), SiMe3, of an ylidyl-selenophosphonyl dichloride (11b), and of 12 have been analyzed. They provide representatives for the full range of rotation from the symmetric conformer with two equal PX bonds to the conformer with one PX bond perpendicular to the PCP plane and with this bond being extremely elongated. Thus, they map out the pathway to PX bond breaking. On this way the initial charge transfer from the ylidic carbon to the antibonding PX orbital ends up in a π donation and PX dissociation.

Structural characterization of a (+)-trans-anti-benzo[a]pyrene-DNA adduct using NMR, restrained energy minimization, and molecular dynamics.

Abstract: The (+)-trans-anti-benzo[a]pyrene adduct formed at the N2 amino group of guanine is the major adduct found after metabolic activation of the ubiquitous carcinogen benzo[a]pyrene. The carcinogenic and mutagenic properties of the (+)-trans-anti-BP adduct, as well as related adducts, have been extensively studied. A DNA duplex containing a (+)-trans-anti-benzo[a]pyrene adduct covalently attached to the G8 nucleotide in the sequence d(CCTATGT[BP-G]CAC).d(GTGCACATAGG) was synthesized and the structure characterized by one- and two-dimensional NMR spectroscopy, in conjunction with energy minimization and molecular dynamics. This BP-11-mer duplex exhibits NOESY cross-peaks between benzo[a]pyrene protons and BP-G8, C9, A16, and C17 nucleotide protons that clearly delineate the location of the BP moiety in the minor groove of a B-type duplex with the pyrene ring oriented toward the 5' end of the modified strand. Large upfield shifts of A16 and C17 sugar resonances in the partner strand show that the pyrene moiety is situated near these sugars. Analysis of the spectra was complicated by the presence of chemical exchange line broadening of protons located near the (...T[BP-G]C...).(...GCA...) adduct site which shows the presence of a minor conformation for this BP-modified duplex in which TA is the 5' neighboring base pair. Distance restraints determined from NOESY spectra recorded at 20 degrees C were used in restrained and unrestrained energy minimization and molecular dynamics simulations to obtain a structure characteristic of the predominant conformation of the BP-11-mer duplex. The important structural features of the BP-11-mer are similar to those reported by Cosman et al. [(1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918] for a (+)-trans-anti-BP adduct at a (...C[BP-G]C...).(...GCG...) sequence in which CG is the 5' neighboring base pair. No evidence of a conformational equilibrium was reported in this duplex, from which we conclude that the presence of a 5' TA base pair plays a role in the conformational equilibrium. Watson-Crick base pairing is retained in the predominant conformer of the (+)-trans-anti-BP modified duplex, which provides a visualization of a structure that could allow faithful replication. The exchange rate could not be slowed sufficiently to allow individual distance parameters to be obtained for the minor conformer.(ABSTRACT TRUNCATED AT 400 WORDS)

Conformational Analysis of Poly(propylene oxide) and Its Model Compound 1,2-Dimethoxypropane

Abstract: Conformational characteristics of poly(propylene oxide) (PPO) and its model compound, 1,2-dimethoxypropane (1,2-DMP), have been investigated. For 1,2-DMP, ab initio molecular orbital (MO) calculations at the MP2/6-31+G*, MP2/6-311+G*, and MP4/6-31+G* levels were carried out, and the free energies and dipole moments of all the possible conformers were evaluated. The bond conformations and the average dipole moments were calculated from the MO data and compared with the corresponding experimental values. The MO calculations, in general, reproduced the observations quite well. The unknown parameters in the Karplus equation expressing the dihedral-angle dependence of the vicinal coupling constant 3 J COCH were determined by comparison of the 3 J COCH values observed for 1,2-DMP with those calculated from the MO results. The free energies were broken down into conformational energy contributions corresponding to first-, second-, and third-order intramolecular interactions. All the first-order-interaction energies were found to be positive. On the other hand, the second-(E ω1 and E ω2 ) and third-(E χ ) order-interaction energies, which reflect nonbonded C-HO...D contacts, were found to be negative ; for example, the E ω1 , E ω2 , and E χ values determined for gaseous 1,2-DMP at the MP2/6-31+G* level are -1.236, -1.884, and -1.266 kcal mol -1 , respectively. As pointed out for 1,2-dimethoxyethane, the gauche stability of the C-C bond in the O-C-C-O sequence appears to arise from the nonbonded C-H...0 interactions. Using the rotational isomeric state (RIS) scheme with up to third-order interactions, the characteristic ratio and dipole moment ratio of isotactic PPO were calculated and found to be in good agreement with the observations.

Ab initio conformational analysis of ethylene glycol and 1,3-propanediol

Abstract: In this study we report the results of an ab initio investigation of the conformational properties of ethylene glycol and 1,3-propanediol. We performed HF/6-31++G ∗∗ optimizations of the geometries of 10 ethylene glycol conformers, and HF/4-31+G ∗ optimizations of 23 1,3-propanediol conformers. In the case of ethylene glycol we found the lowest energy conformers to have a gauche OCCO arrangement, stabilized by intramolecular hydrogen bonding. In case of 1,3-propanediol the lowest energy conformers have gauche OCCC arrangements. Intramolecular hydrogen bonding also plays an important role in this molecule. In both molecules we found that the ab initio results agree relatively well with available experimental data. It was also found that the conformational trends in the smaller ethylene glycol molecule are maintained in the larger 1,3-propanediol molecule. The introduction of Moller-Plesset second order electron correlation strengthens the intramolecular hydrogen bonding and the gauche-effect in both molecules.

A molecular mechanical model that reproduces the relative energies for chair and twist‐boat conformations of 1,3‐dioxanes

Abstract: We present molecular mechanics calculations on the conformational energies of several 2,2-dimethyl-trans-4,6-disubstituted-1,3-dioxanes. Previous studies by Rychnovsky et al.1 have suggested that the relative conformational energies of chair and twist-boat forms of these 1,3-dioxanes were poorly represented by the molecular mechanical models MM2* and MM3* (MacroModel2 implementations of MM2 and MM3) both when compared to experiment and to high-level quantum mechanical calculations. We have studied these molecules with a molecular mechanical force field which features electrostatic-potential-based atomic charges. This model does an excellent job of reproducing the relative conformational energies of the highest level of theory (MP2/6-31G*) applied to the problem. Furthermore, when empirically corrected using the MP2/6-31G* relative conformational energies of the unsubstituted compound 2,2,4-trimethyl-1,3-dioxane, the absolute energy differences calculated with this new model between the chair and twist-boat conformers for five substituted compounds are within an average of 0.30 kcal/mol of the MP2/6-31G* values. The correlation with experiment is also very good. One can, however, modify the initial molecular mechanical model with a single V1(OCOC) torsional potential and do an excellent job in reproducing the absolute conformational energies of the dioxanes as well, with an average error in conformational energies of 0.45 kcal/mol. This same torsional potential was independently developed by comparing ab initio and molecular mechanical energies of the molecule 1,1-dimethoxymethane. Thus, we have succeeded in developing a general molecular mechanical model for 1,3-dioxoalkanes. In addition, we have compared the standard MM2 and MM3 models with MM2* and MM3* (ref. 2) and have found some significant differences in relative conformational energies between MM2 and MM2*. MM2 has an improved correlation with the best ab initio data compared to MM2* but is still significantly worse than that found with lower-level ab initio or AM1 semiempirical quantum mechanics or the new molecular mechanical model presented here. MM3 leads to conformational energies very similar to MM3*. Energy component analysis suggests that the single most important element in reproducing the conformational equilibrium is the electrostatic energy. This fact rationalizes the success of AMBER models, whose fundamental tenet is the accurate representation of quantum mechanically calculated molecular electrostatic effects. © 1995 by John Wiley & Sons, Inc.