The Consistent Force Field. 5. PEF95SAC: Optimized Potential Energy Function for Alcohols and Carbohydrates

Fabricius, Jesper; Engelsen, Søren B.; Rasmussen, Kjeld

doi:10.1080/07328309708006539

Cited by 24 publications

(21 citation statements)

References 52 publications

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“…The aglycon structure was minimized with the Merck Molecular Force Field (MMFF94x), while the sugar unit was minimized with the empirical consistent force field Potential Energy Function for Alcohols and Carbohydrates PEF95SAC. [65] Two rotamers corresponding to energy minima were calculated with the triazole ring and the optimized torsion angle C-C-N-N was determined to be near 08. This constrained angle forces the final structure to be less flattened, resulting in a minimized repulsion between all six branches, together with a larger distance from each sugar.…”

Section: General Procedures For "De-o-acetylation" (Zempløn Reaction)mentioning

confidence: 99%

Combining Glycomimetic and Multivalent Strategies toward Designing Potent Bacterial Lectin Inhibitors

Chabre

Giguère

Blanchard

et al. 2011

Chemistry A European J

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As part of ongoing activities toward the design of potent and selective ligands against galactoside-binding proteins from animal, bacterial, and plant lectins, a systematic investigation involving the synthesis and binding evaluations of a series of original β-C-galactopyranoside mimetics is described. The multivalent presentation of partly optimized candidates on various dendritic scaffolds through Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAc) has also been achieved. Biophysical investigations based on isothermal titration calorimetry (ITC) have indicated a dissociation constant in the low micromolar range for the best optimized monovalent conjugate (K(d)=37 μM). The results thus confirmed that stable C-galactosides could represent efficient synthetic glycomimetics of natural α-linked oligosaccharidic inhibitors of PA-IL lectin (Lec A) from the pathogenic Pseudomonas aeruginosa. Striking enhancements in the avidity of the glycoconjugates were also observed for tri-, hexa-, and nonavalent derivatives, among which the most potent exhibited dissociation constants below 500 nM, corresponding to a 400-fold increase in affinity compared with the β-D-Gal-O-Me used as reference. To deepen our understanding of the binding mode of the best glycomimetics involved in the recognition process, molecular modeling studies, docking calculations, and NMR diffusion measurements have been performed. Although favorable complementary interactions induced by the addition of the hydrophobic aglycon might explain the affinity enhancement, experimental determination of the size and the topology of the multivalent conjugates further supported the formation of aggregative complexes as a major multivalent binding mode. This work represents a systematic and comprehensive study towards a thorough understanding of the protein-carbohydrate interactions involved in Pseudomonas aeruginosa infection, and as such should prove useful for the development of stable and optimized anti-adhesive agents.

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Section: General Procedures For "De-o-acetylation" (Zempløn Reaction)mentioning

confidence: 99%

Combining Glycomimetic and Multivalent Strategies toward Designing Potent Bacterial Lectin Inhibitors

Chabre

Giguère

Blanchard

et al. 2011

Chemistry A European J

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“…Several efforts have been made to set up force fields to reproduce the specific features of carbohydrates. 55,[61][62][63][64][65][66][67][68] Modeling of CDs, just like other oligosaccharides, involves a particular problem regarding the electrostatic representation. Charge sets in carbohydrate force fields have been often derived based either on small fragments 62,65 or on the glucose molecule.…”

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confidence: 99%

Revisiting the internal conformational dynamics and solvation properties of cyclodextrins

Pereira¹,

Moura²,

Freitas³

et al. 2007

J. Braz. Chem. Soc.

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Simulações de dinâmica molecular são utilizadas para investigar a dinâmica conformacional interna e propriedades de solvatação das três ciclodextrinas naturais, α-, β-e γ-ciclodextrina em água e temperatura ambiente. Estes oligossacarídeos derivados da glicose apresentam uma estrutura molecular peculiar que lhes confere a habilidade de formar complexos de inclusão e modificar as propriedades físico-químicas das moléculas complexadas. As características estruturais das ciclodextrinas em solução são determinantes para a complexação. As análises das trajetórias obtidas mostram que ligações de hidrogênio secundárias entre resíduos de glicose adjacentes estão presentes em solução e apresentam um caráter altamente dinâmico, onde ligações de hidrogênio alternativas podem ser formadas com moléculas de água. Apesar do baixo caráter hidrofílico, as cavidades apresentam-se solvatadas e o número de moléculas de água dentro da cavidade é aproximadamente duplicada por unidade de glicose adicionada ao macrociclo. Os tempos de residência para as moléculas de água dentro das cavidades são inversamente proporcionais ao seu respectivo tamanho.Molecular dynamics simulations were used to investigate the internal conformational dynamics and solvation properties of the three natural cyclodextrins, α-, β-and γ-cyclodextrin in aqueous solution at room temperature. These glucose-derived oligosacharides present a molecular structure that confers them the ability to complex guest molecules and change their physicochemical properties. The structural behavior of cyclodextrins in solution is crucial for their complexation abilities. Analyses of the obtained trajectories show that inter-glucose hydrogen bonds between the secondary hydroxyl groups are present in solution, but show a very dynamical character where alternative hydrogen bonds to water molecules can be formed. Despite the lower hydrophilicity of the cyclodextrins inner-cavities, they were found to be solvated and the number of water molecules inside the cavity roughly doubles per glucose unit added to the ring. The residence times for water molecules inside the cavities are inversely proportional to the cavity size. Keywords: cyclodextrins, molecular dynamics, solvation, flexibility IntroductionCyclodextrins (CDs) have been extensively studied since their discovery in the late nineteenth century.1 Their peculiar properties and behavior have interested scientists in many different fields.2 These cyclic oligosaccharides, obtained from starch by glucanotransferase degradation, are formed by a certain number of α-D-glucopyranose units linked by α(1→4) glycosidic bonds. This arrangement produces a truncated cone shape with a central cavity relatively hydrophobic and an external surface relatively hydrophilic.1-3 Naturally occurring CDs, known as α-, β-and γ-CD, present six, seven and eight glucose units, respectively.1-3 The structural features of these saccharides allow them to form inclusion complexes with a great variety of compounds.3 Due to their ability to form host-guest complexe...

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“…Exact charge neutralization is always secured. The algorithm has been described in some detail, 12 as has the choice of dielectric constant. 10 -12 …”

Section: Main Approachesmentioning

confidence: 99%

“…This has been documented in much detail. 9 The present paper records further tests of the force fields, and directions for improvement are indicated.…”

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confidence: 98%

Consistent Force Fields for Saccharides

Rasmussen

1999

Journal of Carbohydrate Chemistry

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Consistent force fields for carbohydrates were hitherto developed by extensive optimization of potential energy function parameters on experimental data and on ab initio results. A wide range of experimental data is used: internal structures obtained from gas phase electron diffraction and from x-ray and neutron diffraction, vibrational frequencies, dipole moments, unit cell dimensions and lattice energies. The range of model compounds covered so far includes alkanes, ethers, alcohols, ketones and mono-and disaccharides. Electrostatic interactions are handled by fractional charges assigned to individual atoms. Charges are modeled such that Mulliken population analyses are reproduced. Morse functions are used for all bonded interactions; experimentally derived dissociation energies are used as parameters. Van der Waals interactions are modeled with Lennard-Jones 12-6 functions. The anomeric and exo-anomeric effects are accounted for without addition of specific terms. The work is done in the framework of the Consistent Force Field which originated in Israel and was further developed in Denmark. The actual methods and strategies employed have been described previously. Extensive testing of the force field is reported, and ways and means of improvement are indicated. Principles of mapping of conformational space are discussed, and a discussion on which properties to preferentially reproduce in modeling is invited. SHORT HISTORY OF THE CFF ATTEMPTSWe have worked on the Consistent Force Field 3 for thirty years, 4 and tried to apply the method to saccharides for twenty; the previous history has been published. 5 The full power of the CFF was not available in its updated form until 1985, 6 and then optimization 789 T 790 RASMUSSEN was undertaken. In 1991 we finished the first serious bid for an optimized force field for carbohydrates and their derivatives, PEF91L. 7Until then we had worked with hand-fitted force fields like most other researchers in modeling, and our main results were the demonstration that relaxation in all internal degrees of freedom is necessary for meaningful calculation of conformations of disaccharides and, by implication, of oligosaccharides; and the proof that quite good results can be provided even with rather primitive potential energy functions, if their parameters are judiciously chosen.PEF91L was applied to a variety of problems, notably the charting of the conformational space of gentiobiose. 7Our work over the years had shown that it was of overriding importance to model the non-bonded interactions adequately. We developed a new and more rational strategy of optimization, 8 involving heavy optimization on crystal structures, which resulted in our best potential energy function so far, with the parameter set PEF95SAC. This has been documented in much detail. 9The present paper records further tests of the force fields, and directions for improvement are indicated.

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The Consistent Force Field. 5. PEF95SAC: Optimized Potential Energy Function for Alcohols and Carbohydrates

Cited by 24 publications

References 52 publications

Combining Glycomimetic and Multivalent Strategies toward Designing Potent Bacterial Lectin Inhibitors

Combining Glycomimetic and Multivalent Strategies toward Designing Potent Bacterial Lectin Inhibitors

Revisiting the internal conformational dynamics and solvation properties of cyclodextrins

Consistent Force Fields for Saccharides

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