Molecular Mechanics Energy Research Articles

Exploration of disaccharide conformations by molecular mechanics

Conformational analyses by molecular mechanics of two-bond linked, glucose-glucose and some glucose-fructose disaccharides are reviewed. Usually, the conformations found by diffraction studies of crystals of relevant molecules were in low-energy regions on φ,ψ surfaces computed with mm3. However, several sucrosyl linkages had energies high above the global minimum. Also, the distributions of experimental conformations did not conform well to the energy surfaces for sucrose and, to a lesser extent, maltose. A new map for maltose, made with mm3(92), had less low-energy area wherein crystal structures were not found, and a miniature crystal model accounts for the remaining distortions Of φ and ψ as well as the short O4…O1 distances in crystalline maltose. An internally consistent calculation of the lattice energy (−76kcalmor −1) required a dielectric constant of 2.5, and values around 3 also worked well for various intramolecular and intermolecular parameters and the φ,ψ map of maltose. The problems with sucrose were not resolved despite further study. The high molecular mechanics energy for some of the sucrosyl linkages may arise from failure to account for an overlapping exo-anomeric effect.

QSRR in Liquid Chromatography Aided by Computational Chemistry

Abstract A quantitative structure-retention relation in reversed-phase liquid chromatography was studied with values calculated by computational chemistry. These values were Van der Waals volume and surface area, calculated by MOPAC-BlogP, total energy calculated by Molecular Mechanics (MM2), kinetic, potential and total energies calculated by Molecular Dynamics (MD), and total energy and dipole moment calculated by Extended Huckel theory (EH). The precision of predicted retention time of non-ionic compounds is improved by using these values instead of Van der Waals volume calculated by Bondi's method and derealization energy from literature.

Molecular mechanics and semiempirical molecular orbital calculations on zinc complexes with amino acid derivatives

Geometry optimisation calculations using semiempirical molecular orbital and molecular mechanics methods on tetrahedral zinc complexes with derivatives of the amino acids cysteine, histidine and glutamic acid have been performed. Charge interaction terms, based on a semiempirical calculation of partial atomic charges, are found to dominate the molecular mechanical steric energy. Geometries optimised by molecular mechanics show better agreement with crystallographic results than do those obtained by the modified neglect of differential overlap method. The final steric energy values show a large variation between the complexes of the derivatives of cysteine, histidine and glutamic acid.

Structural characterization of an N-acetyl-2-aminofluorene (AAF) modified DNA oligomer by NMR, energy minimization, and molecular dynamics.

An N-acetyl-2-aminofluorene (AAF) modified deoxyoligonucleotide duplex, d(C1-C2-A3-C4-[AAF-G5]-C6-A7-C8-C9).d(G10-G11-T12-G13-C14-++ +G15-T16-G17-G18), was studied by one- and two-dimensional NMR spectroscopy. Eight of the nine complementary nucleotides form Watson-Crick base pairs, as shown by NOEs between the guanine imino proton and cytosine amino protons for G.C base pairs or by an NOE between the thymine imino proton and adenine H2 proton for A.T base pairs. The AAF-G5 and C14 bases show no evidence of complementary hydrogen bond formation to each other. The AAF-G5 base adopts a syn conformation, as indicated by NOEs between the G5 imino proton and the A3-H3' and A3-H2'/H2" protons and by NOEs between the fluorene-H1 proton of AAF and the G5-H1' or C6-H1' proton. The NOEs from the C4-H6 proton to C4 sugar protons are weak, and thus the glycosidic torsion angle in this nucleotide is not well defined by these NMR data. The remaining bases are in the anti conformation, as depicted by the relative magnitude of the H8/H6 to H2' NOEs when compared to the H8/H6 to H1' NOEs. The three base pairs on each end of the duplex exhibit NOEs characteristic of right-handed B-form DNA. Distance restraints obtained from NOESY data recorded at 32 degrees C using a 100-ms mixing time were used in conformational searches by molecular mechanics energy minimization studies. The final, unrestrained, minimum-energy conformation was then used as input for an unrestrained molecular dynamics simulation. Chemical exchange cross peaks are observed, and thus the AAF-9-mer exists in more than a single conformation on the NMR time scale. The NMR data, however, indicate the presence of a predominant conformation (> or = 70%). The structure of the predominant conformation of the AAF-9-mer shows stacking of the fluorene moiety on an adjacent base pair, exhibiting features of the base-displacement [Grunberger, D., Nelson, J. H., et al. (1970) Proc. Natl. Acad. Sci. U.S.A. 66, 488-494] and insertion-denaturation models [Fuchs, R.P.P., & Daune, M. (1971) FEBS Lett. 14, 206-208], while the distal ring of the fluorene moiety protrudes into the minor groove.

Transitions of saturated monoacid triglycerides: Modeling conformational change at glycerol during α→β′→β transformation

The glycerol region geometry of modeled saturated monoacid triglycerides was altered by bond rotations and minor angle distortions to convert theoretical α‐forms into bent β′‐ and β‐forms. Direct α to β conversion involves lateral disruption of fatty chain packing to generate side‐chain character typical of the β‐form. Such disruption, which could contribute to fat bloom, allows additional molecular movement and shifts in molecular mechanics energy (MME) that may approximate thermal changes observed by differential scanning calorimetry during α to β transformations. Energy calculations at 100 points throughout each transformation identified plausible conversion routes. A two‐stage conversion, α to either of two stereospecific β′‐forms bent at glycerol followed by subsequent conversion to β, showed less chain movement and more favorable MME than direct α to β conversion. The preferred path, based on energy profiles of each conversion, involves a β′‐D form and rotation of carbonyl to α‐carbon bonds in chain #2 and a side chain (chain #3).

Optimization of parameters of nonbonded interactions in a spectroscopically determined force field

A procedure is given by which parameters of nonbonded interactions in a molecular mechanics energy function can be optimized for maximum compatibility with ab initio force fields and structures. The method is based on a previously derived transformation of ab initio valence parameters to the molecular mechanics formalism. Explicit analytical expressions for the derivatives of the molecular mechanics force constants and reference geometry parameters with respect to the parameters of the nonbonded interactions are derived. The form of the goodness-of-fit function is discussed. A first application to a set of alanine dipeptides is described.

Conformational analysis by molecular mechanics energy minimizations of the tetrapeptide Boc-Gly-Leu-Gly-Gly–NMe, a recurring sequence of elastin

The amino acid sequences Gly-X-Gly-Gly (X = Ala, Val, Leu, lle) frequently recur in elastin and might play a role in the molecular mechanism of protein elasticity. In this paper we report on a theoretical conformational analysis by molecular mechanics energy minimizations of the tetrapeptide Boc-Gly-Leu-Gly-Gly–NMe, using a strategy based on the build-up method for searching exhaustively the conformational space. The set of 3785 conformers has been determined and a statistical analysis has been carried out. The conformers' energy, end-to-end distance, torsions and CO ⋯ HN interaction distance distributions are discussed. The stability of type II β-turn Gly-1-CO ⋯ HNGIy-4, within the conformer family (experimentally observed), and C7 HNLeu-2, C7 HNMe and C10 HNMe hydrogen bonds (hypothesized according to experimental results), have been theoretically verified. The possible role of librational motions and sliding β-turns for the entropic elasticity mechanism of elastin is discussed.

Solution conformation of mono‐ and difucosyllactoses as revealed by rotating‐frame NOE‐based distance mapping and molecular mechanics and molecular dynamics calculations

AbstractThe solution conformation of two fucosyllactoses, Fucα(1 → 2)Galβ(1 → 4)Glcα,β and Galβ(1 → 4) [Fucα(1 → 3)] Glcα,β, and a difucosyllactose, Fucα(1 → 2)Galβ(1 → 4)[Fucα(1 → 3)]Glcα,β, were investigated in Me2SO‐d6 with the use of distance mapping, molecular mechanics (MM) energy minimization and molecular dynamics (MD) simulations. The distance mapping procedure, which was based on rotating‐frame NOE constraints involving C‐ and O‐linked protons, and hydrogen bonding constraints, suggested the occurrence of two conformations for each of the fucose residues. The MM calculations resulted in two minima that were located reasonably near to the regions demarcated in the Θ, Ψ conformational space by distance mapping; 500 ps MD trajectories showed transitions between two conformations characterized by glycosidic angles Θ and Ψ that only deviated insignificantly from those found by the first two methods. No similar transitions were observed for the Galβ14Glc linkage.

A Molecular Mechanics Investigation of RNA Complexes. I. Ethidium Intercalation in an HIV-1 TAR RNA Sequence with an Unpaired Adenosine

Nucleic acid complexes with ethidium intercalated into different sites in a segment of HIV-1 TAR RNA with an unpaired A base, along with corresponding complexes with a normal RNA sequence without an unpaired base were studied by molecular mechanics energy minimization methods. Different intercalation geometries as well as different orientations of the ethidium molecule in the intercalation sites were tested. A general binding affinity enhancement for the ethidium binding to the bulge sequence compared with the normal RNA segment was obtained. With the unpaired adenosine base stacked in the duplex, the binding site adjacent to the 3' side of the bulge was found to be the most energetically favorable binding site, and the intercalation site 5' to the bulge in the same sequence is much less favorable. Unique correlated backbone conformational changes on binding of ethidium to the intercalation site 3' to the bulge were found to relieve backbone strains caused by the stacking of the unpaired base into the helix. These backbone conformational changes present a plausible molecular basis for the experimentally observed ethidium binding preference in this bulge RNA segment (L.S. Ratmeyer, R. Vinayak, G. Zon and W.D. Wilson, J. Med. Chem. 35, 966, 1992).

Molecular dynamics of serotonin and ritanserin interacting with the 5-HT 2 receptor

A three-dimensional model of the serotonin (5-hydroxytrytamine; 5-HT) 5-HT 2 receptor was constructed from the amino acid sequence by molecular graphics techniques, molecular mechanics energy calculations and molecular dynamics simulations. The receptor model has 7 α helical segments which form a membrane-spanning duct with a putative ligand binding site. Most of the synaptic domains and the ligand binding site were surrounded by negative electrostatic potentials, suggesting that positively charged ligands are attracted to the receptor by electrostatic forces. The cytoplasmic domains, except the C-terminal tail, had mainly positive electrostatic potentials. The molecular dynamics of the receptor — ligand complex was examined in 100 ps simulations with 5-HT or ritanserin at a postulated binding site. During the simulations the helices moved from an initial circular arrangement into a more oval arrangement, and became slightly tilted relative to each other. The protonated ligands neutralized the negative electrostatic potentials around Asp 120 and Asp 155 in the central core of the receptor. 5-HT had only weak interactions with Asp 155 but strong interactions with Asp 120 during the simulations, with the amino group of 5-HT tightly bound to the carboxylic side chain of Asp 120. Ritanserin showed similarly strong interactions with Asp 120 and Asp 155 during the simulations.

Comparison of ab initio, semiempirical, and molecular mechanics calculations for the conformational analysis of ring systems

AbstractThe potential energy surfaces of four cyclic alkanes have been examined using molecular mechanics, semiempirical, and ab initio methods to determine if they produce mutually consistent results and investigate the source of any errors between the methods. The C5  C8 cyclic alkanes were chosen since these structures present a finite set of conformations and transition‐state geometries and are still within the computational time and memory limits of the quantum mechanical approaches. We also examined several conformations of 1,2‐dideoxyribose to determine the effect of heteroatoms on the results for the 5‐membered ring. The molecular mechanics and ab initio calculations are consistent in the relative energies and geometries determined for the conformers of all ring systems. While the semiempirical calculations yielded geometries consistent with the other methods (except for 5‐membered rings), the relative energies often deviated substantially. A decomposition analysis of the semiempirical and molecular mechanics energies revealed that the disparities are mainly due to errors in the 1‐center energies of the semiempirical calculations. The 2‐center bonding and nonbonding energies followed reasonable trends for the conformers. The core‐repulsion function, however, is suspected of producing anomalies. A minimum in the attractive Gaussian of this term at 2.1 Å for HH interactions partly explains the propensity of the 5‐membered rings to optimize to near planarity (decreasing 1,2‐diaxial hydrogen distances to 2.3 Å) and the underestimation of the relative energy of the boat structure of cyclohexane.

Computer modeling of packing arrangements and transitions in saturated‐cis‐unsaturated mixed triglycerides

Conformational analysis of modeledcis‐unsaturated chains in triunsaturated and symmetrical monounsaturated triglycerides has identified pseudo‐linear chain orientations that allow lower molecular mechanical energies than are possible with conventionalcis‐chains. Energy plots recorded during bond rotations near the double bond show that energy barriers between linear and normalcis‐configurations are often less than 5 Kcal/mol. Pseudo‐linear orientations, which allow compatible side‐by‐side packing of saturated and unsaturated chains in double‐chainlength mixed triglycerides, also provide a route for efficient transformation between double‐chainlength and triple‐chainlength configurations in solid polymorphic triglycerides.

DAISY, a computational method: a novel tool for the study of the conformational behavior of flexible molecules

daisy, a novel method for obtaining information about conformational potential energy (hyper) surface (PES) paths, has been developed. It consists of two main parts. The first part is logical, based on a heuristic prediction of possible interconversions between conformations. The second part uses an energy computation program for verification of the interconversions predicted in the first part. The current versions of daisy are based on molecular mechanics energy computation. A new molecular descriptor, the conformational softness F 0, is introduced and calculated for a number of molecules. Application of the method to computation of the conformational potential energy hypersurface paths of several molecules is presented. The method can also be extended to a study of reaction PESs.

Application of the molecular simulation technique for clarification of the α .tautm. β phase transformation in poly(butylene terephthalate)

The unit cells of the α and β forms of PBT have been simulated using a molecular mechanics energy minimization approach. Unit-cell parameters derived from the simulated cells compare favorably with those determined experimentally as do calculated X-ray diffraction patterns. From the simulated structures, itt is clear that the change in c-axis length upon transforming from α to β can only be explained in terms of a conformational change of the tetramethylene units from a crumpled to extended state.

Eicosatetraynoic and arachidonic acid-induced changes in cell membrane fluidity consonant with differences in computer-aided design-structures

ETYA (5,8,11,14-eicosatetraynoic acid), a competitive analogue of arachidonic acid (AA), inhibits the proliferation of U937 (human monoblastoid) and PC3 (human prostate) cancer cells, without the overt cytotoxicity associated with AA at similar concentrations. The mechanism of inhibition is not established. ETYA at 100 μM acutely increased whole cell and isolated microsomal membrane fluidity of both cell lines to a greater extent than arachidonic acid. PC3 cells incubated with ETYA for 72 h evidenced increased membrane fluidity. This was measured by the fluorescence polarization parameter, R, using the probes TMA-DPH and DPH for whole cell and isolated membrane fractions, respectively. Compared with whole cells, isolated membranes yielded a 10–20-fold increase in fluorescence intensity. The intramolecular conformational profiles of both ETYA and AA were explored using a combination of molecular mechanics energy minimization and molecular dynamics simulation. While it is possible that not all of the low energy conformational states of either molecule were sampled, the large number of low-energy conformers determined for ETYA correspond to kink deformed conformers relative to the family of AA conformers. These kinks make the molecular cross sections of ETYA larger than AA and arise from the four alkyne bond geometries. This structural finding is consistent with ETYA's greater effect on membrane fluidity. Dissociation between the extent of change in membrane fluidity due to ETYA or AA and inhibition of DNA synthesis can suggest that either (A) increased fluidity and inhibition of DNA synthesis are independent, or as we believe more likely, (B) greater membrane fluidity evoked by ETYA is important for inhibiting DNA synthesis, while changes induced by AA are insufficient or differ qualitatively from those required to initiate and sustain these nonlethal events.

Inclusion of solvation free energy with molecular mechanics energy: alanyl dipeptide as a test case.

A combined force field of molecular mechanics and solvation free energy is tested by carrying out energy minimization and molecular dynamics on several conformations of the alanyl dipeptide. Our results are qualitatively consistent with previous experimental and computational studies, in that the addition of solvation energy stabilizes the C5 conformation of the alanyl dipeptide relative to the C7.

Nuclear Overhauser Effect Spectroscopy (NOESY) and Dihedral Angle Measurements in the Determination of the Conformation of Taxol in Solution

Abstract The 300 MHz 1H-NMR and 75 MHz 13C-NMR spectral assignments of taxol were made with the aid of APT and DEPTGL 1-D spectra and COSY, HETCOR, and NOESY 2-D spectra. In addition to being useful for spectral line assignments, the cross-peaks in the phase-sensitive NOESY spectrum were also used to estimate the distances between protons located on adjacent ring systems of taxol by measuring the volume integration of the cross-peaks. Key dihedral angles of taxol were also estimated using a Karplus-type equation that takes into account the heteroatom substitution on the adjacent carbon atoms. Using the proton-proton distances and the dihedral angles as a guide, molecular mechanics energy minimization molecular modeling was used to arrive at a structure of taxol that was consistent with the NMR data. While the X-ray data for taxol was not available, the NMR data and the molecular modeling results were compared to the X-ray data for taxotere, a close structural analog of taxol that has slightly more biologi...

A molecular modeling study of nucleoside analogues as potential anti-AIDS drugs

Cyclic and acyclic thymidine analogues may act as anti-human immunodeficiency virus agents. Several structures have been optimized using molecular mechanics, and electronic properties calculated using the modified neglect of differential overlap method. Introduction of an unsaturated bond into the ribose ring leads to a large increase in strain energy, but the quantum mechanical heat of formation remains reasonable. Electrostatic potentials were calculated based on partial atomic charges, and compared with the potential around thymidine. It is found that a common region of positive potential exists in the C3' region for the active compounds, and on this basis the unsynthesized acyclic compounds studied here may be active. In azidothymidine (AZT) the extent of twist around the N1-C1' bond determines the presence or absence of this feature. A relationship is found to exist between the molecular mechanics energy and the EC50 activity data for the azido-substituted compounds.

The relationship between anesthetic potency (minimum alveolar concentration) and molecular shape; structural studies on conventional inhalational anesthetics.

We have explored the ability of molecular mechanics energy calculation as a probe to obtain quantitative information about the molecular shape and energies of inhalational anesthetics. (Molecular mechanics is a readily accessible, nonquantum mechanical method of computing detailed molecular structure from energetical viewpoint.) From this aspect, the structure-activity relationships of ten inhalational anesthetics were studied. Using this method, stable conformers of these anesthetics are deduced with various physicochemical parameters. The importance of dipole interaction as the major determinant of stable conformation was suggested, and reasonable correlations between anesthetic potency (minimum alveolar concentration: MAC) and components of dipole moments, with reference to the specific sites of molecules, were obtained. The results indicate that there are important polar components which play a major role in anesthesia.

A new strategy for the evaluation of force parameters from quantum mechanical computations

AbstractA new strategy for the determination of force parameters is presented. The equilibrium values appearing in the force field equations representing the “stretching” and “bending” of bonds are directly determined from quantum mechanical calculations without geometrical restrictions. The determination of the force parameters is carried out by means of a rigorous fitting between the quantum mechanic and the molecular mechanical energy variations arising from the perturbation of the geometric variables. The strategy presented here has been incorporated into a computer program named PAPQMD, which was developed in order to provide nonquantum mechanical experts with a powerful tool for the determination of approximate force parameters. The program was developed upon the assumption that force parameters are not universal, but they strongly depend on the molecular environment. This implies that the parametrization procedure should be done in a molecular model close to the molecule or molecules to be studied by means of molecular mechanical or dynamic methods, and consequently, it is no longer supposed that the variation of one geometrical parameter does not affect the rest of the molecular geometry. PAPQMD performs the fitting between molecular mechanics and quantum mechanical energies considering all the perturbations that the modification in one geometric variable causes in all the others, enabling the parametrization even of large molecules. The ability of our method to reproduce experimentally derived force parameters is discussed and compared with the widely used Hopfinger's strategy. The study of the behavior of PAPQMD and Hopfinger's strategies for reproducing the force parameters of two complex molecules demonstrates the superiority of the methodology presented here.