Relationship among ligand conformations in solution, in the solid state, and at the Hsp90 binding site: geldanamycin and radicicol

The unknown effects of a receptor's environment on a ligand's conformation presents a difficult challenge in predicting feasible bioactive conformations, particularly if the receptor is ill-defined. The primary hypothesis of this work is that a structure's conformational ensemble in solution presents viable candidates for protein binding. The experimental solution profile can be achieved with the NAMFIS (NMR analysis of molecular flexibility in solution) method, which deconvolutes the average NMR spectrum of small flexible molecules into individual contributing conformations with varying populations. Geldanamycin and radicicol are structurally different macrocycles determined by X-ray crystallography to bind to a common site on the cellular chaperone heat shock protein 90 (Hsp90). Without benefit of a receptor structure, NAMFIS has identified the bioactive conformers of geldanamycin and radicicol in CDCl3 solution with populations of 4% and 21%, respectively. Conversely, docking the set of NAMFIS conformers into the unliganded proteins with GLIDE followed by MM-GBSA scoring reproduces the experimental crystallographic binding poses.     

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

The 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.     

Synthesis, Conformational Studies, X-ray Structures, and Complexation Properties of Semirigid Macrocyclic Phosphonamides

The semirigid phosphonamide ligands 1-5 have been synthesized from the macrocyclic precursors 6-9 by reaction with 1,3-propanediol ditosylate or 1,2-dichloroethane. For the thiophosphoryl compounds 1 and 2, and the phosphoryl derivative 5, the reactions were carried out in biphasic aqueous NaOH solutions. The phosphoryl derivatives 3 and 4 were better obtained from NaH in anhydrous tetrahydrofuran. The conformations of the hosts in solution were deduced from low-temperature NMR and NOE difference experiments. Conformational equilibria between exo and endo forms are observed for the 18-membered macrocycles 1 and 3. The exo conformer predominates in solution for the 21-membered macrocycle 2, whereas 4 exists as rapidly exchanging conformers. The X-ray crystal structures of macrocycles 1, 2, and 5 have been determined as well as the complexes 1.Hg(SCN)(2) and 5.LiNO(3). In the Hg(2+) complex the metal ion is located out of the macrocyclic cavity and is coordinated to the thiophosphoryl unit. In 5.LiNO(3)()()the Li(+) cation is located inside the macrocyclic cavity and is coordinated to a tetrahedral array of oxygen donors. Free energies of complexation (DeltaG degrees ) of the phosphorylated ligands 3-5 with alkali metal and ammonium cations were determined in CHCl(3) saturated with H(2)O by picrate extraction experiments. The -DeltaG degrees values are greatest for 4 complexing K(+) and NH(4)(+) (7.3 and 8.0 kcal/mol, respectively). The relationships between structure and binding are discussed.     

Metal induced folding: synthesis and conformational analysis of the lanthanide complexes of two 44-membered hydrazone macrocycles

Six new lanthanide complexes of two 44-membered macrocycles have been prepared and characterised in solution. An analysis of the conformations of the free macrocycles and their lanthanide complexes both in solution (2D NMR) and in solid state (X-ray crystallography) demonstrate that the complexation induces changes in folding of the macrocycles.     

Conformational Analysis of p-Substituted Calix[6]arenes by Molecular Mechanics and Quantum-Chemical Methods

The molecular mechanics (AMBER 3.0) and quantum-chemical (AM1) calculations indicated that in the series of calix[6]arenes substituted on the upper rim, the preferable conformation is a pinched cone stabilized by the nonequivalent hydrogen bonds on the lower rim of the macrocycle molecule. For the basic conformers of the macrocycles under study, the endocyclic dihedral angles between the planes of the benzene rings characterizing the shape of the macrocycles were calculated. The results of AM1 and AMBER 3.0 calculations agree with the results of the conformational analysis of calix[6]arene molecules by experimental and theoretical methods.     

Theoretical models for the conformations and the protonation of triacetonamine

Summary In this paper we propose theoretical models for the conformations of triacetonamine and protonated triacetonamine (Vincubine, an anticancer chemotherapeutic agent) developed by quantum and molecular mechanics techniques. We discuss the theoretical factors which are involved in the stabilization of the conformations calculated by the MNDO, MM2 and COPEANE methods and show the relative percent abundance of each molecular shape. Graphic representations of the conformers are depicted.     

Accurate predictions of water cluster formation, (H₂O)(n=2-10)

An efficient mixed molecular dynamics/quantum mechanics model has been applied to the water cluster system. The use of the MP2 method and correlation consistent basis sets, with appropriate correction for BSSE, allows for the accurate calculation of electronic and free energies for the formation of clusters of 2-10 water molecules. This approach reveals new low energy conformers for (H(2)O)(n=7,9,10). The water heptamer conformers comprise five different structural motifs ranging from a three-dimensional prism to a quasi-planar book structure. A prism-like structure is favored energetically at low temperatures, but a chair-like structure is the global Gibbs free energy minimum past 200 K. The water nonamers exhibit less complexity with all the low energy structures shaped like a prism. The decamer has 30 conformers that are within 2 kcal/mol of the Gibbs free energy minimum structure at 298 K. These structures are categorized into four conformer classes, and a pentagonal prism is the most stable structure from 0 to 320 K. Results can be used as benchmark values for empirical water models and density functionals, and the method can be applied to larger water clusters.     

Computational analysis of the potential energy surfaces of glycerol in the gas and aqueous phases: effects of level of theory, basis set, and solvation on strongly intramolecularly hydrogen-bonded systems.

The 126 possible conformations of 1,2,3-propanetriol (glycerol) have been studied by ab initio molecular orbital and density functional theory calculations in the gas and aqueous phases at multiple levels of theory and basis sets. The partial potential energy surface for glycerol as well as an analysis of the conformational properties and hydrogen-bonding trends in both phases have been obtained. In the gas phase at the G2(MP2) and CBS-QB3 levels of theory, the important, low-energy conformers are structures 100 and 95. In the aqueous phase at the SM5.42/HF/6-31G* level of theory, the lowest energy conformers are structures 95 and 46. Boltzmann distributions have been determined from these high-level calculations, and good agreement is observed when these distributions are compared to the available experimental data. These calculations indicate that the enthalpic and entropic contributions to the Gibbs free energy are important for an accurate determination of the conformational and energetic preferences of glycerol. Different levels of theory and basis sets were used in order to understand the effects of nonbonded interactions (i.e., intramolecular hydrogen bonding). The efficiency of basis set and level of theory in dealing with the issue of intramolecular hydrogen bonding and reproducing the correct energetic and geometrical trends is discussed, especially with relevance to practical computational methods for larger polyhydroxylated compounds, such as oligosaccharides.     

Relevance of torsional effects to the conformational equilibria of 1,5-diaza-cis-decalins: a theoretical and experimental study

1,5-Diaza-cis-decalin populates two conformations in which the nitrogen atoms are either gauche (N-in) or anti (N-out) to one another. The equilibrium mixture of the two conformers depends on the substituents at the nitrogen atom, as well as the reaction conditions. Ab initio (HF/6-31G, B3LYP/6-31+G) and molecular mechanics (Amber) calculations have been performed to examine the possible role of stereoelectronics and steric effects in controlling the equilibrium of substituted 1,5-diaza-cis-decalins. In the present study, N,N'-diethyl- and N,N'-bistrifluoroethyl-1,5-diaza-cis-decalins have been synthesized, and the equilibrium mixtures have been measured using 1H and 13C NMR experiments. Steric effects appear to control the equilibria between the two conformational isomers of 1,5-diaza-cis-decalin while torsional effects appear to dominate the equilibria for the N,N'-dialkyl derivatives.     

Studies on structure and conformational stability of free canonical 2′‐deoxyribonucleosides: Approximate SCC‐DFTB and LMP2 methods

The molecular structure of free canonical 2′‐deoxyribonucleosides have been studied by applying the electron‐correlated local second‐order Møller–Plesset perturbation theory (LMP2) and self‐consistent‐charge density‐functional tight‐binding (SCC‐DFTB) methods. The variation of structural parameters for C2, C3 endo and exo conformations, and anti, syn orientation of the base unit with furanose ring have been discussed. The relative energies have been calculated for the anti and syn conformations of dT, dC, dG, and dA. Conformational analysis has been performed using the results of the LMP2 and SCC‐DFTB methods. Chemical hardness and chemical potential have been used to study the conformational stability of the conformers. The maximum hardness principle is obeyed for the furanose ring conformations and not for the nucleosides. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2004     

Conformational study of the cholinergic agonist pilocarpidine,isopilocarpidine, and related species

A conformational study on the energies and geometries of the stable conformers of the cholinergic agonist pilocarpidine and of its inactive isomer, isopilocarpidine, has been carried out by molecular mechanics MM2 and by semiempirical quantum chemical AM1. The former predicts an envelope conformation of the -lactone nucleus, whereas AM1 predicts a planar conformation. The relative energies of the different conformations of both isomers are strongly dependent on the relative orientation of the imidazole moiety. Other related species, intermediate steps in their synthesis, and the anion intermediate in the epimerization are also discussed.     

Determination of the major solution conformation of tyrocidine A,using molecular mechanics energy minimization and NMR-derived distance and torsion angle constraints

Molecular mechanics energy calculations coupled with nuclear magnetic resonance-determined distance and torsion angle constraints have been used to determine the three-dimensional structure of tyrocidine A, a cyclic decapeptide which exists largely as a single conformation in solution. Two open-chain polyalanine models were used to represent separate halves of the peptide backbone and a combinatorial method of searching conformation space used to generate candidate structures consistent with experimental distance constraints. These structures were energy-minimized using the AMBER molecular mechanics forcefield and the resulting conformations classified by factor analysis of their Cartesian coordinates. Representative low-energy conformers of the two halves of the backbone were fused together and two candidate conformations of the completed backbone refined by further minimization using both distance and torsional constraints. Side chains were then added as their experimentally preferred rotamers and the whole molecule minimized without constraints to give the final model structure. This shows type II' and III ß turns at residues 4–5 and 9–10, respectively, coupled by twisted antiparallel strands which show hydrogen bonds between all four pairs of opposing peptide groups. The backbone conformation of residues 2–6 closely resembles that found in the crystal structure of gramicidin S.     

Different approaches to conformational analysis: A comparison of completeness,efficiency, and reliability based on the study of a nine-membered lactam

Different methods such as molecular dynamics, systematic, or stochastic search and a special “generic shape” algorithm have been employed in the conformational analysis of a nine-membered lactam. Furthermore, crystal data were used to generate conformations of the compound under consideration. The various methods are compared in terms of their efficiency and completeness in the search for conformations with an energy content of up to 60 kJ/mol above the global minimum. Additionally, the generated conformations have been optimized by different techniques, molecular mechanics and quantum chemical calculations, to compare the number of existing local minima and their relative energies and geometries.     

Intramolecular interaction energies in model alanine and glycine tetrapeptides. Evaluation of anisotropy, polarization, and correlation effects. A parallel ab initio HF/MP2, DFT, and polarizable molecular mechanics study

An extension of the SIBFA polarizable molecular mechanics procedure to flexible oligopeptides is reported. The procedure is evaluated by computing the relative conformational energies, deltaE(conf), of the alanine tetrapeptide in 10 representative conformations, which were originally derived by Beachy et al. (J Am Chem Soc 1997, 119, 5908) to benchmark molecular mechanics procedures with respect to ab initio computations. In the present study, a particular emphasis is on the separable nature of the components of the energy and the particular impact of the polarization energy component on deltaE(conf). We perform comparisons with respect to single-point HF, DFT, LMP2, and MP2 computations done at the SIBFA-derived energy minima. Such comparisons are made first for the 10 conformers derived from phi/psi torsional angle energy-minimization (the rigid rotor approach), and, in a second step, after allowing additional relaxation of the C(alpha) centered valence angles. In both series of energy-minimization, the SIBFA deltaE(conf) compared best with the LMP2 results using the 6-311G** basis set, the rms being 1.3 kcal/mol. In the absence of the polarization component, the rms is 3.5 kcal/mol. In both series of minimizations, the magnitudes of deltaE(conf), computed as differences with respect to the most stable conformer taken as energy zero, decrease along the series: HF > DFT > LMP2 > SIBFA > MP2, indicative of increasing stabilization of the most highly folded conformers.     

Selectivity of bis(calix[4]diquinone) ionophores towards metal ions in solvent dimethylsulfoxide: a molecular mechanics and molecular dynamics study

Molecular modelling studies have been carried out on two bis(calix[4]diquinone) ionophores, each created from two (calix[4]diquinone)arenes bridged at their bottom rims via alkyl chains (CH(2))(n), 1: n = 3, 2; n = 4, in order to understand the reported selectivity of these ligands towards different sized metal ions such as Na(+), K(+), Rb(+), and Cs(+) in dmso solution. Conformational analyses have been carried out which show that in the lowest energy conformations of the two macrocycles, the individual calix[4]diquinones exhibit a combination of partial cone, 1,3-alternate and cone conformations. The interactions of these alkali metals with the macrocycles have been studied in the gas phase and in a periodic box of solvent dmso by molecular mechanics and molecular dynamics calculations. Molecular mechanics calculations have been carried out on the mode of entry of the ions into the macrocycles and suggest that this is likely to occur from the side of the central cavity, rather than through the main axis of the calix[4]diquinones. There are energy barriers of ca. 19 kcal mol(-1) for this entry path in the gas phase, but in solution no energy barrier is found. Molecular dynamics simulations show that in both 1 and 2, though particularly in the latter macrocycle, one or two solvent molecules are bonded to the metal throughout the course of the simulation, often to the exclusion of one or more of the ether oxygen atoms. By contrast the carbonyl oxygen atoms remain bonded to the metal atoms throughout with bond lengths that remain significantly less than those to the ether oxygen atoms. Free energy perturbation studies have been carried out in dmso and indicate that for 1, the selectivity follows the order Rb(+) approximately K(+) > Cs(+) > Na(+), which is partially in agreement with the experimental results. The energy differences are small and indeed the ratio between stability constants found for Cs(+) and K(+) complexes is only 0.60, showing that has only a slight preference for K(+). For the larger receptor , which is better suited to metal complexation, the binding affinity follows the pattern Cs(+) > Rb(+) > K(+) > Na(+), with energy differences of 5.75, 2.61, 2.78 kcal mol(-1) which is perfectly consistent with experimental results.     

Self-assembly of metallamacrocycles using a dinuclear organometallic acceptor: synthesis, characterization, and sensing study

A dinuclear organometallic acceptor 4,4'-bis[trans-Pt(PEt(3))(2)(O(3)SCF(3))(ethynyl)]biphenyl (1) containing Pt-ethynyl functionality is synthesized. Multinuclear NMR ((1)H, (31)P, and (13)C), infrared (IR), and electrospray ionization mass spectrometry (ESI-MS) including single-crystal X-ray diffraction analysis established the formation of 1. Equimolar treatment of acceptor 1 separately with three different "clip" type ditopic donors (L(a)-L(c)) yielded [2 + 2] self-assembled three metallamacrocycles 2a-2c, respectively. These macrocycles were characterized by various spectroscopic techniques, and their sizes/shapes were obtained through geometry optimization using molecular mechanics universal force field (MMUFF) simulations. Attachment of unsaturated ethynyl functionality to biphenyl building unit helped to make the macrocycles (2a-2c) π-electron rich and thereby fluorescent in nature. Furthermore, 2c in solution has been examined to be suitable for sensing electron-deficient nitroaromatic like picric acid, which is often considered as a secondary chemical explosive. The fluorescence study of 2c showed a marked quenching of initial emission intensity upon titrating with picric acid (PA), and it exhibited the largest fluorescence quenching response with high selectivity among various other electron deficient aromatic compounds tested.     

Computational study of urea and its homologue glycinamide: conformations, rotational barriers, and relative interactions with sodium chloride

Conformational behaviors of urea and glycinamide have been investigated using the B3LYP functional with the 6-311+G* and 6-311+G** basis sets. Urea monomers have nonplanar minima at all the levels studied, even in the aqueous phase. In the case of glycinamide, the intramolecular hydrogen bond formed from the amide to the amine is important for stabilizing the global minimum. Bond rotations and nitrogen inversion barriers for glycinamide conformations have also been reported. The DFT calculated results suggest that urea conformers interact preferentially with the {111} surface of sodium chloride and such interactions can be responsible for the change in the habit of sodium chloride. Glycinamide conformers have a lower affinity toward the {111} surface of sodium chloride in water. The pyramidality of nitrogens in urea conformers does not influence the relative trends of interaction energies with sodium chloride surfaces. The mode of interactions predicted at the LDA/PWC/DND level for urea and glycinamide with sodium chloride for both slab and cluster models shows that the amide functionality (-CONH2) interacts with both Na(+) and Cl(-) ions on the {100} surface; however, the carbonyl oxygen of these additives predominantly interacts with the sodium ions on the {111} surface.     

Computational protocols for prediction of solute NMR relative chemical shifts. a case study of L-tryptophan in aqueous solution

In this study, we have applied two different spanning protocols for obtaining the molecular conformations of L-tryptophan in aqueous solution, namely a molecular dynamics simulation and a molecular mechanics conformational search with subsequent geometry re-optimization of the stable conformers using a quantum mechanically based method. These spanning protocols represent standard ways of obtaining a set of conformations on which NMR calculations may be performed. The results stemming from the solute-solvent configurations extracted from the MD simulation at 300 K are found to be inferior to the results stemming from the conformations extracted from the MM conformational search in terms of replicating an experimental reference as well as in achieving the correct sequence of the NMR relative chemical shifts of L-tryptophan in aqueous solution. We find this to be due to missing conformations visited during the molecular dynamics run as well as inaccuracies in geometrical parameters generated from the classical molecular dynamics simulations.     

Efficient proton-templated synthesis of 18- to 38-membered tetraimino(amino)diphenol macrocyclic ligands: structural features and spectroscopic properties

A whole range of Robson-type tetraiminodiphenol macrocyclic ligands have been prepared as their perchlorate salts [H4L](ClO4)2 in high yield (ca. 90%) by a single-step [2 + 2] condensation reaction between 4-methyl(or tert-butyl)-2,6-diformyl(or diacyl)phenols and alpha,omega-diaminoalkanes (C2-C12) in the presence of acetic acid and NaClO4. The reduction of these 18- to 38-membered macrocyclic salts with NaBH4 have afforded corresponding tetraaminodiphenol macrocycles H2L'. The X-ray crystal structures of two of the tetraiminodiphenol macrocycles with the C2 and C4 lateral chains have been determined, and the optimized configurations for all of the macrocycles have been obtained by molecular mechanics calculations. The macrocycles have been characterized by elemental analysis and by IR, absorption, emission, and NMR spectroscopic study. The protonated tetraiminodiphenol macrocycles exhibit strong fluoroscence in methanol, acetonitrile, and nitromethane and undergo quenching when treated with triethylamine. The neutral macrocycles H2L, isolated by treating [H4L](ClO4)2 with excess of triethylamine, lack luminescence, as do the reduced tetraaminodiphenol macrocycles H2L'. The hydrolytic cleavage of [H4L](ClO4)2 has been studied.