Molecular Mechanics Energy Minimization Research Articles

A decoy set for the thermostable subdomain from chicken villin headpiece, comparison of different free energy estimators

BackgroundEstimators of free energies are routinely used to judge the quality of protein structural models. As these estimators still present inaccuracies, they are frequently evaluated by discriminating native or native-like conformations from large ensembles of so-called decoy structures.ResultsA decoy set is obtained from snapshots taken from 5 long (100 ns) molecular dynamics (MD) simulations of the thermostable subdomain from chicken villin headpiece.An evaluation of the energy of the decoys is given using: i) a residue based contact potential supplemented by a term for the quality of dihedral angles; ii) a recently introduced combination of four statistical scoring functions for model quality estimation (FRST); iii) molecular mechanics with solvation energy estimated either according to the generalized Born surface area (GBSA) or iv) the Poisson-Boltzmann surface area (PBSA) method.ConclusionThe decoy set presented here has the following features which make it attractive for testing energy scoring functions:1) it covers a broad range of RMSD values (from less than 2.0 Å to more than 12 Å);2) it has been obtained from molecular dynamics trajectories, starting from different non-native-like conformations which have diverse behaviour, with secondary structure elements correctly or incorrectly formed, and in one case folding to a native-like structure. This allows not only for scoring of static structures, but also for studying, using free energy estimators, the kinetics of folding;3) all structures have been obtained from accurate MD simulations in explicit solvent and after molecular mechanics (MM) energy minimization using an implicit solvent method. The quality of the covalent structure therefore does not suffer from steric or covalent problems.The statistical and physical effective energy functions tested on the set behave differently when native simulation snapshots are included or not in the set and when averaging over the trajectory is performed.

A simple low-cost simulation protocol for approximate localization of structural water molecules in DNA oligonucleotides

Using a computational low-cost protocol by combining molecular mechanics energy minimization and molecular dynamics employing the OPLS-AA force field, we were able to reproduce the main structural features of the first hydration shell of double-helix DNA hetero-oligonucleotides in the A (1DPL) and B-conformations (1DPN and 1ENN), whose coordinates are available with atomic resolution from crystallographic data. Our simple protocol also reproduced the main hydration patterns of DNA homo-oligonucleotides in the B-conformation [(AT)12 and (CG)12], obtained before by computer simulation using a longer and more sophisticated molecular dynamics protocol. A preliminary model of the first hydration shell of oligonucleotides may be very useful to those interested in performing quantum-mechanical calculations of systems where hydration features are unknown at the molecular level; the model may also be used by crystallographers during refinement steps.

The Importance of Being Exhaustive. Optimization of Bridging Structural Water Molecules and Water Networks in Models of Biological Systems

Algorithms and protocols are described for the optimization for H-bonding of isolated singular H2O molecules and entire networks of H2O molecules. Unlike other approaches that are prone to being trapped in local energy minima, these methods rely on exhaustive searches of orientation space for the H2O molecules. The results are scored with the HINT hydropathic interaction model, but the algorithms should be general for any energy-scoring computation. Two examples are provided: 1) the tightly-bound H2O molecule 301 of HIV-1 protease is shown to be more reasonably oriented in terms of forming H-bonds with this method than with a molecular mechanics energy minimization method; and 2) the H2O network surrounding carbonmonoxymyoglobin is constructed and analyzed for a 1.80-A neutron-diffraction structure. The H-atom positions calculated with this method show a somewhat better agreement with the experimental results than do the H-atom positions calculated with molecular mechanics, and both are considerably better than random.

Salts of aromatic carboxylates: the crystal structures of nickel(II) and cobalt(II) 2,6-naphthalenedicarboxylate tetrahydrate

The crystal structures of isostructural 2,6-naphthalenedicarboxylate tetrahydrate salts of nickel(II) and cobalt(II) have been determined using Monte Carlo simulated annealing techniques and laboratory X-ray powder diffraction data. These compounds crystallize in the triclinic space groupP\bar{1}, withZ= 2;a= 10.0851 (4),b= 10.9429 (5),c= 6.2639 (3) Å, α = 98.989 (2), β = 87.428 (3), γ = 108.015 (2)°,V= 649.32 (5) Å3for [Ni(C12H6O4)(H2O)4], anda= 10.1855 (6),b= 10.8921 (6),c= 6.2908 (5) Å, α = 98.519 (4), β = 87.563 (4), γ = 108.304 (3)°,V= 655.28 (8) Å3for [Co(C12H6O4)(H2O)4]. The water-molecule H atoms were located by quantum chemical geometry optimization usingCASTEP. The structure consists of alternating hydrocarbon and metal/oxygen layers parallel to theacplane. Each naphthalenedicarboxylate anion bridges two metal cations; each carboxyl group is monodentate. The resulting structure contains infinite chains parallel to [111]. The octahedral coordination sphere of the metal cations containstranscarboxylates and four equatorial water molecules. The carboxyl groups are rotated by 15–20° out of the naphthalene plane. The metal/oxygen layers are characterized by an extensive hydrogen-bonding network. The orientations of the carboxyl groups are determined by the formation of short (O...O = 2.53 Å) hydrogen bonds between the carbonyl O atoms and theciswater molecules. Molecular mechanics energy minimizations suggest that coordination and hydrogen-bonding interactions are most important in determining the crystal packing.

Wittig reactions on photoprotoporphyrin IX: new synthetic models for the special pair of the photosynthetic reaction center.

A first example of spirochlorin-chlorin dimer with fixed distances and orientations as potential model for the "special pair" of the photosynthetic reaction center is discussed. For the preparation of such a novel structure, the Wittig reagent of the desired "spacer" 5 was reacted with photoprotoporphyrin IX dimethyl ester 3 to produce the intermediate dimer 6, which on intramolecular [4 + 2] Diels-Alder cycloaddition gave an unexpected spirochlorin-chlorin dimer 9. Dehydration of dimer 6 under acid-catalyzed conditions generated the corresponding spirochlorin-porphyrin dimer 16 in quantitative yield. The asymmetry in dimer 6 caused by the biphenyl-type anisotropic effect was confirmed by NMR and model studies. The formation of dihydrobenzoporphyrin 14 by reacting chlorin 3 with the phosphonium salt of p-methylbenzylbromide 10 and isolation of 8-phenanthrenevinylporphyrin 19 from chlorin 7 further confirmed our proposed mechanism for the formation of a spirochlorin-chlorin dimer 9. Following a similar approach, chlorin 3 on reacting with bis-phosphonium salt of 4, 4'-bischloromethylbiphenyl produced conjugated chlorin dimer 25. The spectroscopic data obtained from these dimers suggest that, in these compounds, the individual chromophores are not behaving as an individual molecule, but as a single macrocycle. To examine whether the pi-pi interaction exhibited by dimer 9 resembles the structural arrangement of bacteriochlorophylls in reaction center (RC), we investigated the geometrical parameters used to characterize the pi-pi interactions in tetrapyrrolic macrocycles. Starting from the crystallographic coordinates of 9, the molecular mechanics energy minimization was performed to obtain the model dimer structure. The geometrical parameters that measure the single pyrrole ring overlap were used to compare the model structure with the crystallographic coordinates of the special pair in photosynthetic reaction center. The results indicated that the ring A of spirochlorin and the ring C of chlorin in our model dimer 9 mimic the ring A-ring A interaction found in the crystallographic special pairs, which are strategically placed by the surrounding photosynthetic reaction center protein matrix.

Conformational analysis of the major DNA adduct derived from the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline.

The heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is one of a number of carcinogens found in barbecued meat and fish. It is mutagenic in bacterial and mammalian assays and induces tumors in mammals. IQ is biochemically activated to a derivative which reacts with DNA to form a major covalent adduct at carbon 8 of guanine. This adduct may deform the DNA and consequently cause a mutation, which may be responsible for initiating IQ's carcinogenicity. Atomic resolution structures of the IQ-damaged DNA are not yet available experimentally. We have carried out an extensive molecular mechanics energy minimization search to locate feasible structures for the major IQ-DNA adduct in the representative sequence d(5'-G1-G2-C3-G4-C5-C6-A7-3'). d(5'-T8-G9-G10-C11-G12-C13-C14-3') with IQ modification at G4; this contains the GGCGCC mutational hotspot sequence known as NarI. The molecular mechanics program AMBER 5.0 with the force field of Cornell et al. [(1995) J. Am. Chem. Soc. 117, 5179-5197] was employed, including explicit Na(+) counterions and an implicit treatment for solvation. However, key parameters, the partial charges, bond lengths, bond angles, and dihedral parameters of the modified residue, are not available in the AMBER database. We carefully parametrized the force field, created 800 starting conformations which uniformly sampled at 18 degrees intervals each of the three flexible torsion angles that govern the IQ-DNA orientation, and minimized their energy. A conformational mix of structural types, including major groove, minor groove, and base-displaced intercalated carcinogen positions, was generated. This mixture may be related to the diversity of mutational outcomes induced by IQ.

Synthesis, modeling and binding affinity of an ester analogue of the terminal trisaccharide of the tumor-associated antigen globo-H

The synthesis of the trisaccharide α- l-Fuc p-(1→2)-β- d-Gal p-(1→3)-β- d-Gal p2 AcO Pr ( 3), mimicking the globo-H terminal trisaccharide unit ( 2), is described. The conformational properties of 3 were investigated with the aid of molecular mechanics energy minimizations, molecular dynamics simulations, and 1H-NMR spectroscopic analysis and resulted in strict analogy with those of 2. Nevertheless, analysis of MBr1 binding to these compounds indicate that substitution of the acetamido group at C-2 with the ester group lowers the affinity, thus suggesting that the amide hydrogen atom of 2 is involved in intermolecular interactions with the MBr1 antibody.

Characterization of the bioactive form of linear peptide antagonists at the omega-opioid receptor.

The stereochemical requirements for omega-opioid receptor binding of a series of linear peptide antagonists with a novel conformationally restricted Phe analogue (Tic) as a second residue were examined by using a variety of computational chemistry methods. The omega-opioid receptor analogues with significant affinity, Tyr-Tic-NH2(TI-NH2), Tyr-Tic-Phe-OH(TIP), Tyr-Tic-Phe-NH2(TIP-NH2), Tyr-Tic-Phe-Phe-OH(TIPP), Tyr-Tic-Phe-Phe-NH2)(TIPP-NH2), and the low affinity omega-opioid peptides Tyr-Pro-Phe-Pro-NH2(morphiceptin) and Tyr-Phe-Phe-Phe-NH2 (TPPP-NH2), were included in this study. The conformational profiles of these peptides were obtained by consecutive cycles of high and low temperature molecular dynamic stimulations, coupled to molecular mechanical energy minimization carried out until no new conformational minima were obtained. Comparing the results for TPPP-NH2 and TIPP-NH2, the presence of the conformationally restricted Tic residue did not greatly reduce the number of unique low energy conformations, but did allow low energy conformers involving cis bonds between the first two residues. The conformational libraries of these peptides were examined for their ability to satisfy the three key ligand components for receptor recognition already identified by previous studies of high affinity cyclic (Tyr1-D-Pen2-Gly3-Phe4-D-Pen5) enkephalin (DPDPE) type agonists: a protonated amine group, an aromatic ring, and a lipophilic moiety in a specific geometric arrangement. Two types of conformations common to the five high omega-opioid affinity L-Tic analogues were found that satisfied these requirements, one with a cis and the other with a trans peptide bond between the Tyr1 and Tic2 residues. Moreover, both the Tic2 and Phe3 residues could mimic the hydrophobic interactions with the receptor of the Phe4 moiety in the cyclic DPDPE type agonists, consistent with the appreciable affinity of both di- and tripeptides. The low omega-opioid receptor affinity of morphiceptin can be understood as the result of conformational preferences that prevent the fulfillment of this pharmacophore for recognition.

A Composite from Poly(m-phenylenevinylene-co-2,5-dioctoxy-p-phenylenevinylene) and Carbon Nanotubes: A Novel Material for Molecular Optoelectronics

As research progresses towards smaller and more efficient devices, the need to develop alternative molecular scale electronic materials becomes apparent. Integrated electronic component fabrication from organics has been recognized theoretically as the ultimate goal. In order to gain a comprehensive insight into these materials, extensive research has been carried out on conjugated carbon systems over the last few decades to optimize their optical and electrical properties. For example, doping polyacetylene with I2 has been shown to result in a large increase in conductivity compared to the pristine material. However, doping polymers tends to retard their optical properties as regards luminescence by reducing their bandgaps and introducing trapping sites such as solitons, polarons, or bipolarons. The simple lesson over the years is that if materials are to be considered for luminescence, doping should not be carried out despite the desire to improve charge transport properties. We report here the first physical adopingo, to use the traditional term, using small concentrations of multiwalled nanotubes in a conjugated luminescent polymer, poly(m-phenylenevinylene-co-2,5-dioctoxyp-phenylenevinylene) (PmPV), in a polymer/nanotube composite. This can increase electrical conductivity of the polymer by up to eight orders of magnitude. The nanotubes appear to act as nanometric heat sinks, preventing the buildup of large thermal effects, caused either optically (photobleaching) or electrically, which degrade these conjugated systems. We also report that electroluminescence was achieved from an organic light-emitting diode (LED) using the composite as the emissive layer in the device. Since initial work on conjugated systems, attempts have been made to find an area where polymers and/or fullerenes could be used as active semiconductor components. Although many new and interesting materials have been synthesized to this end, very few have found a practical application. One exception is polyphenylenevinylene (PPV), first reported by Burroughes et al. as being the light-emitting semiconductor in a Schottky diode. This encouraged scientists to study a wide variety of conjugated systems, including derivatives of this polymer, in order to optimize the efficiency of light emission from such devices. Polymers for use in LEDs must possess a number of important qualities. A high quantum yield of photoluminescence is necessary and the material must remain undoped, as dopants act as trapping sites, quenching the radiative decay of excitons. It is essential therefore to find a polymer that is reasonably conductive while maintaining its luminescent properties. Most undoped polymers possess a very low conductivity and so require high aturn-ono fields to generate sufficient carriers in order to produce the excitons, which decay radiatively. This is, in practical terms, very inefficient as fields generally induce large thermal effects, consequently causing device breakdown. There are other problems that must be addressed, but elimination of these very basic ones should substantially improve efficiencies and soon lead to applications for these polymers. The polymer used in our studies is PmPV, whose structure is a variation of the more common PPV. In this case the substitution pattern leads to dihedral angles in the chain and, according to molecular mechanics energy minimization calculations, the polymer chain tends to coil, forming a helical structure. The calculated diameter of this helix in vacuum is ca. 20 Š, whilst the pitch is ca. 6 Š. Multiwalled nanotubes were produced by the arc discharge method, resulting in multiwalled nanotubes of 20 nm average diameter and lengths between 500 nm and 1.5 mm. The nanotube powder and PPV were mixed together in toluene and sonicated briefly. It is probable that the coiled polymer conformation allows it to surround layers of nanotubes, permitting sufficiently close intermolecular proximity for p±p interaction to occur. The color change was dramatic in that the polymer has a bright yellow color while the composite, at high nanotube concentrations, possesses a deep green color. Photoluminescence studies were carried out using an Ar laser at the pump wavelength of 457 nm. Electrical conductivity was measured using a twopoint probe sandwich geometry and Pt electrodes. The LED was fabricated by casting the composite onto indium tin oxide (ITO) then sputtering an aluminum electrode on top. As the polymer structure possesses helicity, it is not surprising that it is able to wrap itself around the nanotubes and keep them suspended in solution indefinitely. The actual texture of the composite can be observed in Figure 1,

Structural characterization of the molecular dimer of the peptide antibiotic vancomycin by distance geometry in four spatial dimensions.

The conformation of a dimer of the peptide antibiotic vancomycin is developed from computer simulations based on experimental distance constraints derived from high-resolution NMR measurements. The conformation and topological array of the dimer are determined by a distance geometry based method using the molecules cast into four spatial dimensions. This method was imperative for the refinement of vancomycin given the entwining of the monomers (including hydrogen bonding and interactions between the aromatic ring systems) within the dimer. The development of the high-resolution structure of the monomer and then simple molecular modeling to create the dimer which fulfills all of the experimental observations was not possible. In contrast, the refinement protocol using the dimer cast into four spatial dimensions was able to quickly locate conformations in which both the intra- and intermolecular nuclear Overhauser effects were satisfied. These structures, once converted back to three dimensions, were further refined using standard molecular mechanics energy minimization. The structural characteristics of the dimer with respect to binding to the cell-wall precursor are described.

Substrate binding and catalytic mechanism in phospholipase C fromBacillus Cereus: A molecular mechanics and molecular dynamics study

For the first time a consistent catalytic mechanism of phospholipase C from Bacillus cereus is reported based on molecular mechanics calculations. We have identified the position of the nucleophilic water molecule, which is directly involved in the hydrolysis of the natural substrate phosphatidylcholine, in phospholipase C. This catalytically essential water molecule, after being activated by an acidic residue (Asp55), performs the nucleophilic attack on the phosphorus atom in the substrate, leading to a trigonal bipyramidal pentacoordinated intermediate (and structurally similar transition state). The subsequent collapse of the intermediate, regeneration of the enzyme, and release of the products has to involve a not yet identified second water molecule. The catalytic mechanism reported here is based on a series of molecular mechanics calculations. First, the x-ray structure of phospholipase C from B cereus including a docked substrate molecule was subjected to a stepwise molecular mechanics energy minimization. Second, the location of the nucleophilic water molecule in the active site of the fully relaxed enzyme-substrate complex was determined by evaluation of nonbonded interaction energies between the complex and a water molecule. The nucleophilic water molecule is positioned at a distance (3.8 A) from the phosphorus atom in the substrate, which is in good agreement with experimentally observed distances. Finally, the stability of the complex between phospholipase C, the substrate, and the nucleophilic water molecule was verified during a 100 ps molecular dynamics simulation. During the simulation the substrate undergoes a conformational change, but retains its localization in the active site. The contacts between the enzyme, the substrate, and the nucleophilic water molecule display some fluctuations, but remain within reasonable limits, thereby confirming the stability of the enzyme-substrate-water complex. The protocol developed for energy minimization of phospholipase C containing three zinc ions located closely together at the bottom of the active site cleft is reported in detail. In order to handle the strong electrostatic interactions in the active site realistically during energy minimization, delocalization of the charges from the three zinc ions was considered. Therefore, quantum mechanics calculations on the zinc ions and the zinc-coordinating residues were carried out prior to the molecular mechanics calculations, and two different sets of partial atomic charges (MNDO-Mulliken and AMI-ESP) were applied. After careful assignment of partial atomic charges, a complete energy minimization of the protein was carried out by a stepwise procedure without explicit solvent molecules. Energy minimization with either set of charges yielded structures, which were very similar both to the x-ray structure and to each other, although using AMI-ESP partial atomic charges and a dielectric constant of 4, yielded the best protein structure.

Ab Initio and Semiempirical Calculations of Geometry and Electronic Spectra of Ruthenium Organic Complexes and Modeling of Spectroscopic Changes upon DNA Binding

A new parameter set for the INDO model is proposed for ruthenium as well as a general way to obtain parameters for any transition metal. The ionic state of the transition metal rather than the atomic state has been used to obtain ionization potentials. A rather large series of ruthenium complexes are treated in this work, ranging from [Ru(NH3)6]2+ to [Ru(phen)2dppz]2+ (phen = phenanthroline, dppz = dipyrido[3,2-a:2‘,3‘-c]phenazine) and the so-called Creuz−Taube ion ([Ru(NH3)5-pyrazine-Ru(NH3)5]4+/5+). In all the complexes, Ru has a formal oxidation state of 2+ or 3+. Geometry optimizations at both ab initio and semiempirical INDO levels are presented. The proposed parametrization of the INDO model reproduces both the geometry and the absorption spectra of ruthenium complexes with good accuracy. Bond length changes upon changing the oxidation state of the metal are not fully reproduced. The ab initio calculations predict Ru−N bond lengths that are 0.1−0.15 Å too long compared to observations. The corresponding bond lengths are calculated in better agreement with observations with the INDO model. The effect upon DNA binding on the calculated spectrum of the [Ru(phen)2dppz]2+ complex was investigated. The DNA binding was modeled by a molecular mechanics energy minimization of a [Ru(phen)2dppz]2+−poly(dA-dT) complex.

A quantitative shape analysis of organic templates employed in zeolite synthesis

Structure analysis has been carried out on 160 organic templating agents known to synthesize zeolites from 27 framework types. Conformations were obtained by molecular mechanics energy minimization and the molecular principal axes of inertia plotted to produce three-dimensional shape-space diagrams. The results show a clear correlation between template shape and the zeolite product formed and give a unique insight into the relationship between large and small templates that produce the same product. This work highlights the potential importance of shape analysis as a strategy in template design.

Modeling of Platinum Clusters in H-Mordenite

The size, location and structure of Pt clusters in H-mordenite have been investigated by molecular mechanics energy minimization and molecular dynamics simulation techniques using the Catalysis software of Molecular Simulations (MSI). Lattice energy minimizations are performed to study the effects of the specific framework aluminum positions on the location and stability of monoatomic Pt sites in H-mordenite. The lattice energies relative to the siliceous platinum-aluminosilicate structure reveal that the stability of a single Pt atom in H-mordenite is remarkably influenced by the specific location of the Al atoms in the lattice. At the studied Si/Al ratio of two Al ions per unit cell, a stabilization of the H-mordenite lattice upon Pt deposition is obtained. Moreover, lattice energy calculations on Pt/aluminosilicate mordenites of different metal contents per unit cell have been performed. An optimum size for the aggregate confined to the 12-ring main channel that is almost independent of the Pt content per mordenite unit cell has been found. The structural features of the resulting clusters at the end of molecular dynamics simulations on Pt/alumina-mordenites reflect a strong metal-zeolite interaction. The present results are consistent with a previous molecular dynamics simulation study on the structure of platinum deposited on SiO2 surfaces.

Characterization of the bioactive form of linear peptide antagonists at the δ‐opioid receptor

The stereochemical requirements for δ-opioid receptor binding of a series of linear peptide antagonists with a novel conformationally restricted Phe analogue (Tic) as a second residue were examined by using a variety of computational chemistry methods. The δ-opioid receptor analogues with significant affinity, Tyr-Tic-NH2 (TI-NH2), Tyr-Tic-Phe-OH (TIP), Tyr-Tic-Phe-NH2(TIP-NH2), Tyr-Tic-Phe-Phe-OH (TIPP), Tyr-Tic-Phe-Phe-NH2) (TIPP-NH2), and the low affinity δ-opioid peptides Tyr-Pro-Phe-Pro-NH2 (morphiceptin) and Tyr-Phe-Phe-Phe-NH2 (TPPP-NH2), were included in this study. The conformational profiles of these peptides were obtained by consecutive cycles of high and low temperature molecular dynamic simulations, coupled to molecular mechanical energy minimization carried out until no new conformational minima were obtained. Comparing the results for TPPP-NH2 and TIPP-NH2, the presence of the conformationally restricted Tic residue did not greatly reduce the number of unique low energy conformations, but did allow low energy conformers involving cis bonds between the first two residues. The conformational libraries of these peptides were examined for their ability to satisfy the three key ligand components for receptor recognition already identified by previous studies of high affinity cyclic (Tyr1-D-Pen2-Gly3-Phe4-D -Pen5) enkephalin (DPDPE) type agonists: a protonated amine group, an aromatic ring, and a lipophilic moiety in a specific geometric arrangement. Two types of conformations common to the five high δ-opioid affinity L-Tic analogues were found that satisfied these requirements, one with a cis and the other with a trans peptide bond between the Tyr1 and Tic2 residues. Moreover, both the Tic2 and Phe3 residues could mimic the hydrophobic interactions with the receptor of the Phe4 moiety in the cyclic DPDPE type agonists, consistent with the appreciable affinity of both di-and tripeptides. The low δ-opioid receptor affinity of morphiceptin can be understood as the result of conformational preferences that prevent the fulfillment of this pharmacophore for recognition. © 1996 John Wiley & Sons, Inc.

Characterization of the bioactive form of linear peptide antagonists at the δ-opioid receptor

The stereochemical requirements for omega-opioid receptor binding of a series of linear peptide antagonists with a novel conformationally restricted Phe analogue (Tic) as a second residue were examined by using a variety of computational chemistry methods. The omega-opioid receptor analogues with significant affinity, Tyr-Tic-NH2(TI-NH2), Tyr-Tic-Phe-OH(TIP), Tyr-Tic-Phe-NH2(TIP-NH2), Tyr-Tic-Phe-Phe-OH(TIPP), Tyr-Tic-Phe-Phe-NH2)(TIPP-NH2), and the low affinity omega-opioid peptides Tyr-Pro-Phe-Pro-NH2(morphiceptin) and Tyr-Phe-Phe-Phe-NH2 (TPPP-NH2), were included in this study. The conformational profiles of these peptides were obtained by consecutive cycles of high and low temperature molecular dynamic stimulations, coupled to molecular mechanical energy minimization carried out until no new conformational minima were obtained. Comparing the results for TPPP-NH2 and TIPP-NH2, the presence of the conformationally restricted Tic residue did not greatly reduce the number of unique low energy conformations, but did allow low energy conformers involving cis bonds between the first two residues. The conformational libraries of these peptides were examined for their ability to satisfy the three key ligand components for receptor recognition already identified by previous studies of high affinity cyclic (Tyr1-D-Pen2-Gly3-Phe4-D-Pen5) enkephalin (DPDPE) type agonists: a protonated amine group, an aromatic ring, and a lipophilic moiety in a specific geometric arrangement. Two types of conformations common to the five high omega-opioid affinity L-Tic analogues were found that satisfied these requirements, one with a cis and the other with a trans peptide bond between the Tyr1 and Tic2 residues. Moreover, both the Tic2 and Phe3 residues could mimic the hydrophobic interactions with the receptor of the Phe4 moiety in the cyclic DPDPE type agonists, consistent with the appreciable affinity of both di- and tripeptides. The low omega-opioid receptor affinity of morphiceptin can be understood as the result of conformational preferences that prevent the fulfillment of this pharmacophore for recognition.

Triurea Derivatives of Diethylenetriamine as Potential Templates for the Formation of Artificial β-Sheets1

This paper describes synthetic and structural studies of triurea derivatives of an N,N"-disubstituted diethylenetriamine. Diethylenetriamine triureas 1 (PhN(CONHR1)CH2CH2N(CONHR2)CH2CH2N(CONHR3)CH2CH2CN; 2a, R1 = R2 = R3 = Ph; 2b, R1 = R2 = R3 = CH3; 2c, R1 = (S)-CH(CH2Ph)CO2CH3, R2 = (S)-CH(i-Pr)CO2CH3, R3 = (S)-CH((S)-s-Bu)CO2CH3)) are efficiently prepared in five or six steps from N-phenylethylenediamine. Infrared spectroscopy, 1H NMR spectroscopy, and X-ray crystallography indicate that triureas 1 adopt intramolecularly hydrogen-bonded conformations, both in chloroform solution and in the solid state. The three urea groups form a hydrogen-bonded network: The carbonyl group of urea NCONHR1 is hydrogen bonded to the NH group of urea NCONHR2, and the carbonyl group of urea NCONHR2 is hydrogen bonded to the NH group of urea NCONHR3. The three R groups are aligned along the triurea backbone, pointing in roughly the same direction, like three fingers on a hand. Molecular modeling suggests that the triurea backbone will be a suitable template for the creation of artificial β-sheets. When molecular mechanics energy minimization calculations are performed upon a triurea bearing three N-terminally linked peptide strands, a parallel β-sheet is formed.

Configuration and Conformation of (3S,3aR,4R,7S,7aS)-4-Methyl-7-(2-propyl)-2-oxo-2,3,3a,4,5,6,7,7a-octahydro-3-benzofurancarboxylic Acid

The crystal structure determination of the title compound, C 13 H 20 0 4 , together with the knowledge of the configuration of the starting menthyl reagent, define both its absolute configuration and that of the menthyl ester from which it is obtained by hydrolysis. The structure of the title compound in the crystal is compared with that obtained for the isolated molecule by molecularmechanics energy minimization. The largest discrepancies are observed for the carboxyl group which, in the crystal, is involved in hydrogen bonding with the same group of an adjacent molecule packed about a twofold axis of the P 2 1 2 1 2 space group. The conformation of the molecule is discussed.

Topological analysis of electron density maps of chiral cyclodextrin-guest complexes: a steric interaction evaluation

This paper reports interaction energy values for the systems heptakis (2,3,6-tri- O-methyl)-β-cyclodextrin complexed with R- and S-flurbiprofen. An intermolecular steric interaction potential calculation method is applied from the topological analysis of electron density maps and is assessed by comparison with values obtained from the application of conventional molecular mechanics energy minimization procedures. Both topology-based and standard energy minimization methods predict that the crystalline form of the R-flurbiprofen is the most stable one.

DNA-DNA interstrand cross-linking by cis-diamminedichloroplatinum(II): N7(dG)-N7(dG) cross-linking at 5′-d(GC) in synthetic oligonucleotides

The nucleotide sequence specificity of the DNA-DNA interstrand cross-linking reaction of cis-diamminedichloroplatinum(II) ( cis-DDP) was studied in synthetic oligonucleotides. Of six self-complementary DNAs tested, only those containing the central sequence 5′-(GC) formed appreciable interstrand cross-linked product, as assayed by denaturing polyacrylamide gel electrophoresis (DPAGE). The nucleotide connectivity of the interstrand cross-link was defined by sequence random oxidative fragmentation followed by DPAGE, revealing that dG residues on opposite strands at the sequence 5′-d(GC) were connected to one another. The covalent structure of the cross-link was established following hydrolysis of the phosphodiester backbone of a structurally homogeneous sample of a cis-DDP interstrand cross-linked DNA tetradecamer. HPLC analysis of the hydrolysate returned all of the deoxynucleoside residues from the starting DNA except for two deoxyguanosine residues. Also returned was diammine-bis-[N7-(2′-deoxyguanosyl)]platinum(II) 2+, identified by a combination of spectroscopic methods, and comparison to a synthetic authentic sample. This study directly establishes that cis-DDP forms interstrand crosslinks at the duplex sequence 5′-d(GC), linking deoxyguanosine residues on opposite strands at N7 through a bridging platinum atom. Computer simulation of the interstrand cross-linked product using molecular mechanics energy minimization and molecular dynamics revealed significant structural reorganization at the site of the cross-link including a ca 40° angle between the platinated guaninyl residues, which propagated to adjacent residues by base stacking to yield duplexes bent by some 30° toward the major groove.