Chiral Recognition of Dansyl Derivatives with an Amino Acid-Based Molecular Micelle: A Molecular Dynamics Investigation.

In this study, the chiral separation mechanisms of Dansyl amino acids, including Dansyl-Leucine (Dans-Leu), Dansyl-Norleucine (Dans-Nor), Dansyl-Tryptophan (Dans-Trp) and Dansyl-Phenylalanine (Dans-Phe) binding to poly-sodium N-undecanoyl-(L)-Leucylvalinate, poly(SULV), were investigated using molecular dynamics simulations. Micellar electrokinetic chromatography (MEKC) has previously shown that when separating the enantiomers of these aforementioned Dansyl amino acids, the L- enantiomers bind stronger to poly(SULV) than the D- enantiomers. This study aims to investigate the molecular interactions that govern chiral recognition in these systems using computational methods. This study reveals that the computationally-calculated binding free energy values for Dansyl enantiomers binding to poly(SULV) are in agreement with the enantiomeric order produced in experimental MEKC studies. The L- enantiomers of Dans-Leu, Dans-Nor, Dans-Trp, and Dans-Phe binding to their preferred binding pockets in poly(SULV) yielded binding free energy values of -21.8938, -22.1763, -21.3329 and -13.3349 kJ·mol-1, respectively. The D- enantiomers of Dans-Leu, Dans-Nor, Dans-Trp, and Dans-Phe binding to their preferred binding pockets in poly(SULV) yielded binding free energy values of -14.5811, -15.9457, -13.6408, and -12.0959 kJ·mol-1, respectively. Furthermore, hydrogen bonding analyses were used to investigate and elucidate the molecular interactions that govern chiral recognition in these molecular systems.

Comparison of Chiral Recognition of Binaphthyl Derivatives with l-Undecyl-Leucine Surfactants in the Presence of Arginine and Sodium Counterions.

In this study the chiral selectivity of l-undecyl-leucine (und-leu) for binapthyl derivatives was examined with the use of arginine and sodium counterions at pH's ranging from 7 to 11. The objective of this project was to investigate whether a cationic amino acid, such as arginine would achieve enhanced chiral selectivity when utilized as the counterion in the place of sodium in micellar electrokinetic chromatography. The data indicate that und-leu has significantly improved chiral selectivity toward 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate (BNP) enantiomers in the presence of arginine counterions in comparison to sodium and that, at least in the case of this study, the enantiomeric form of the arginine did not appear to play a role in the chiral selectivity. The maximum resolution (Rs) achieved for BNP when sodium was used as the counterion was ~0.6. However, when arginine was used as the counterion, the maximum resolution for BNP was ~4.1. This was an increase in resolution of ~ 7-fold. However, no significant difference was observed for the enantiomers of 1,1'-bi-2-naphthol. In order to learn more about why this might be the case, NMR studies were conducted to examine what role the counterion might play in enantiomeric recognition.

Investigation of Chiral Recognition by Molecular Micelles with Molecular Dynamics Simulations.

Molecular dynamics simulations were used to characterize the binding of the chiral drugs chlorthalidone and lorazepam to the molecular micelle poly-(sodium undecyl-(L)-leucine-valine). The project's goal was to characterize the nature of chiral recognition in capillary electrophoresis separations that use molecular micelles as the chiral selector. The shapes and charge distributions of the chiral molecules investigated, their orientations within the molecular micelle chiral binding pockets, and the formation of stereoselective intermolecular hydrogen bonds with the molecular micelle were all found to play key roles in determining where and how lorazepam and chlorthalidone enantiomers interacted with the molecular micelle.

Nuclear Magnetic Resonance Investigation of the Effect of pH on Micelle Formation by the Amino Acid-Based Surfactant Undecyl l-Phenylalaninate.

Micelle formation by the anionic amino acid-based surfactant undecyl l-phenylalaninate (und-Phe) was investigated as a function of pH in solutions containing either Na+, l-arginine, l-lysine, or l-ornithine counterions. In each mixture, the surfactant's critical micelle concentration (CMC) was the lowest at low pH and increased as solutions became more basic. Below pH 9, surfactant solutions containing l-arginine and l-lysine had lower CMC than the corresponding solutions with Na+ counterions. Nuclear magnetic resonance (NMR) diffusometry and dynamic light scattering studies revealed that und-Phe micelles with Na+ counterions had hydrodynamic radii of approximately 15 Å throughout the investigated pH range. Furthermore, l-arginine, l-lysine, and l-ornithine were found to bind most strongly to the micelles below pH 9 when the counterions were cationic. Above pH 9, the counterions became zwitterionic and dissociated from the micelle surface. In und-Phe/l-arginine solution, counterion dissociation was accompanied by a decrease in the hydrodynamic radius of the micelle. However, in experiments with l-lysine and l-ornithine, micelle radii remained the same at low pH when counterions were bound and at high pH when they were not. This result suggested that l-arginine is attached perpendicular to the micelle surface through its guanidinium functional group with the remainder of the molecule extending into solution. Contrastingly, l-lysine and l-ornithine likely bind parallel to the micelle surface with their two amine functional groups interacting with different surfactant monomers. This model was consistent with the results from two-dimensional ROESY (rotating frame Overhauser enhancement spectroscopy) NMR experiments. Two-dimensional NMR also showed that in und-Phe micelles, the aromatic rings on the phenylalanine headgroups were rotated toward the hydrocarbon core of micelle.

Molecular Dynamics Simulation and NMR Investigation of the Association of the ß-Blockers Atenolol and Propranolol with a Chiral Molecular Micelle.

Molecular dynamics simulations and NMR spectroscopy were used to compare the binding of two ß-blocker drugs to the chiral molecular micelle poly-(sodium undecyl-(L)-leucine-valine). The molecular micelle is used as a chiral selector in capillary electrophoresis. This study is part of a larger effort to understand the mechanism of chiral recognition in capillary electrophoresis by characterizing the molecular micelle binding of chiral compounds with different geometries and charges. Propranolol and atenolol were chosen because their structures are similar, but their chiral interactions with the molecular micelle are different. Molecular dynamics simulations showed both propranolol enantiomers inserted their aromatic rings into the molecular micelle core and that (S)-propranolol associated more strongly with the molecular micelle than (R)-propranolol. This difference was attributed to stronger molecular micelle hydrogen bonding interactions experienced by (S)-propranolol. Atenolol enantiomers were found to bind near the molecular micelle surface and to have similar molecular micelle binding free energies.

A Molecular Dynamics Simulation Study of the Association of 1,1'-Binaphthyl-2,2'-diyl hydrogenphosphate Enantiomers with a Chiral Molecular Micelle.

Molecular dynamics (MD) simulations were used to investigate the binding of 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate (BNP) enantiomers to the molecular micelle poly-(sodium undecyl-(L,L)-leucine-valine) (poly(SULV)). Poly(SULV) is used as a chiral selector in capillary electrophoresis separations. Four poly(SULV) binding pockets were identified and either (R)-BNP or (S)-BNP were docked into each pocket. MD simulations were then used to identify the preferred BNP binding site. Within the preferred site, both enantiomers formed hydrogen bonds with poly(SULV) and penetrated into the poly(SULV) core. Comparisons of BNP enantiomer binding to the preferred poly(SULV) pocket showed that (S)-BNP formed stronger hydrogen bonds, moved deeper into the binding site, and had a lower poly(SULV) binding free energy than the (R) enantiomer. Finally, MD simulation results were in agreement with capillary electrophoresis and NMR experiments. Each technique showed (S)-BNP interacted more strongly with poly(SULV) than (R)-BNP and that the site of chiral recognition was near the poly(SULV) leucine chiral center.

A Molecular Dynamics Simulation Study of Two Dipeptide Based Molecular Micelles: Effect of Amino Acid Order.

Molecular dynamics (MD) simulations were used to compare the structures of the chiral molecular micelles (MM) poly-(sodium undecyl-(L,L)-leucine-valine) (poly(SULV)) and poly-(sodium undecyl-(L,L)-valine-leucine) (poly (SUVL)). Both MM contained polymerized surfactant monomers tenninated by chiral dipeptide headgroups. The study was undertaken to investigate why poly(SULV) is generally a better chiral selector compared to poly(SUVL) in electrokinetic chromatography separations. When comparing poly(SULV) to poly(SUVL), poly(SULV) had the more conformational flexible dipeptide headgroup and hydrogen bond analyses revealed that the poly(SULV) headgroup conformation allowed a larger number of intramolecular hydrogen bonds to form between monomer chains. In addition, a larger number of water molecules surrounded the chiral centers of the poly(SULV) molecular micelle. Poly(SULV) was also found to have a larger solvent accessible surface area (SASA) than poly(SUVL) and fluctuations in the poly(SULV) SASA during the MD simulation allowed dynamic monomer chain motions expected to be important in chiral recognition to be identified. Finally, approximately 50% of the Na+ counterions were found in the first three solvation shells surrounding both MM, with the remainder located in the bulk. Overall the MD simulations point to both greater headgroup flexibility and solvent and analyte access to the chiral centers of the dipeptide headgroup as factors contributing to the enhanced chiral selectivity observed with poly(SULV).

Investigation of Chiral Molecular Micelles by NMR Spectroscopy and Molecular Dynamics Simulation.

NMR spectroscopy and molecular dynamics (MD) simulation analyses of the chiral molecular micelles poly-(sodium undecyl-(L,L)-leucine-valine) (poly-SULV) and poly-(sodium undecyl-(L,L)- valine-leucine) (poly-(SUVL)) are reported. Both molecular micelles are used as chiral selectors in electrokinetic chromatography and each consists of covalently linked surfactant chains with chiral dipeptide headgroups. To provide experimental support for the structures from MD simulations, NOESY spectra were used to identify protons in close spatial proximity. Results from the NOESY analyses were then compared to radial distribution functions from MD simulations. In addition, the hydrodynamic radii of both molecular micelles were calculated from NMR-derived diffusion coefficients. Corresponding radii from the MD simulations were found to be in agreement with these experimental results. NMR diffusion experiments were also used to measure association constants for polar and non-polar binaphthyl analytes binding to both molecular micelles. Poly(SUVL) was found to bind the non-polar analyte enantiomers more strongly, while the more polar analyte enantiomers interacted more strongly with poly(SULV). MD simulations in tum showed that poly(SUL V) had a more open structure that gave greater access for water molecules to the dipeptide headgroup region.

Optimization of 12 chiral analytes with 8 polymeric surfactants.

This manuscript discusses the results of studies that were performed to determine optimum capillary electrophoresis (CE) conditions for the enantiomeric resolution of twelve chiral analytes with eight amino acid based polymeric surfactants. The parameters that were optimized include pH, buffer type, and concentration of surfactant. The results indicated that the optimum conditions for enantiomeric separations with the amino acid based polymeric surfactants examined in this study using CE were analyte dependent, not surfactant dependent. In other words, the optimum conditions for a particular analyte were the same for all the amino acid based polymeric surfactants examined in this study. The results of these studies indicate that when using a large group of related amino acid based polymeric surfactants only a few surfactants need to be optimized for each analyte under study. These studies were limited to anionic surfactants that contain the amino acids glycine, L-alanine, L-valine, and L-leucine only. No inference can be necessarily drawn about surfactants containing other types of amino acids such as threonine and serine, which contain extra heteroatoms, or phenylalanine that has an aromatic moiety.

Seasonal variation in the toxicity of sediment-associated contaminants in Corpus Christi Bay, TX.

Seasonal variation in pore water and sediment-water interface (SWI) toxicity at two sites of suspected contamination was investigated using sea urchin embryological development (Arbacia punctulata) and copepod hatching success (Schizopera knabeni). Site S1, located inside a marina, was fine-grained and S2, located near a neighboring stormwater outfall, was sandy. Both sites were cored in summer and winter, along with reference sites of equivalent grain sizes. Whereas the muddy contaminated site displayed a slight decrease in sea urchin toxicity from summer to winter, pore water from the sandy contaminated site exhibited an increase in sea urchin toxicity. The sandy sites displayed slight toxicity increase to copepod hatching success in winter, which occurred in the SWI of S2 and in the pore water from the reference site, R2, where it coincided with sedimentation. Cu was the most prevalent metal in the sediment samples. Although Cu concentration increased in the whole sediments and pore waters from summer to winter, its concentration in overlying SWI exposure decreased from summer to winter. Organic compounds exhibited opposite behavior, with smaller variety identified in the winter pore water samples, but more chemicals detected in the SWI samples in winter.

Chiral separation of norlaudanosoline, laudanosoline, laudanosine, chlorthalidone, and three benzoin derivatives using amino acid based molecular micelles.

In this study, 18 polymeric single amino acid and dipeptide surfactants are examined, and their performances, in terms of enantioselectivity, are compared for norlaudanosoline, laudanosoline, laudanosine, chlorthalidone, benzoin, benzoin methyl, and benzoin ethyl enantiomers. Several aspects of amino acid-based polymeric surfactants including comparison of single amino acid versus dipeptide, amino acid order, steric effect, and effect of the position of the chiral center of dipeptide surfactants on the chiral selectivity of these optically active compounds are discussed.

Chiral recognition of binaphthyl derivatives using electrokinetic chromatography and steady-state fluorescence anisotropy: effect of temperature.

The effect of temperature on the chiral recognition of binaphthyl derivatives in the presence of poly sodium N-undecanoyl-LL-leucyl-leucinate (poly LL-SULL) is examined using electrokinetic chromatography (EKC) and steady-state fluorescence anisotropy. An examination of the effect of temperature suggests that the chiral recognition of 1,1'-binaphthyl-2,2'-diol enantiomers improves with increasing temperature, whereas lower temperatures resulted in better enantiosolectivity in the case of 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate enantiomers. In addition, steady-state fluorescence anisotropy results show that the anisotropy of the two enantiomers are different when complexed to poly-(LL) SULL. As would be expected, the enantiomer that binds stronger to the chiral pseudostationary phase, as evidenced by EKC experiments, had higher anisotropy values. The results of this study suggest that steady-state fluorescence anisotropy can be used to gain further insight into chiral recognition.

Enantiomeric separations using polymeric L-glutamate surfactant derivatives: effect of increasing steric factors.

This study examines the role of steric hindrance near the stereogenic centers of four glutamic acid based polymeric surfactants. The single amino acid surfactants of glutamic acid, glutamic acid methyl ester, glutamic ethyl ester, and glutamic acid tert-butyl ester were investigated. The micellar electrokinetic chromatography (MEKC) separation of three binaphthyl derivatives and three benzodiazepines were used to study these steric factors. In addition, the hydrophobicity of these polymers as a function of pH was investigated by use of fluorescence measurements.

Enantiomeric separations using poly(L-valine) and poly(L-leucine) surfactants. Investigation of steric factors near the chiral center.

This study examined the effect of steric factors near the stereogenic center on polymerized surfactants, sodium N-undecyl-L-leucine, sodium N-undecyl-L-norleucine, sodium N-undecyl-L-tert.-butyl leucine, sodium N-undecyl-L-isoleucine. sodium N-undecyl-L-valine, sodium N-undecyl-L-norvaline. and sodium N-undecyl-L-proline. The effect of steric factors near the chiral center of the polymeric surfactants were examined using binaphthyl derivatives, aminoglutethimide, and 2,2,2-trifluoro-1-(9-anthryl)ethanol. In addition, fluorescence spectroscopy was used to determine the hydrophobicities of these surfactants using the environmentally-sensitive probe pyrene.

Depth of penetration of binaphthyl derivatives into the micellar core of sodium undecenoyl leucyl-leucinate surfactants.

Two different diastereomeric forms of sodium N-undecanoyl leucyl-leucinate (SULL) (both L,L and L,D) are used to examine the role of depth of penetration of chiral analytes into the micellar core of polymeric and monomeric surfactants on enantioselectivity. In this study, chiral separation of three binaphthyl derivatives, i.e. (+/-)-1,1'-bi-naphthyl-2,2'-diamine (BNA), (+/-)-1,1'-bi-2-naphthol (BOH), and (+/-)-1,1'-binaphthyl-2,2'-dihydrogen phosphate (BNP), are studied. Chromatographic results suggest that BNP interacts approximately the same with both the C- and N-terminal amino acid of poly SULL, while the preferential site of interaction of this analyte with the monomeric form of SULL (mono SULL) is at the C-terminal amino acid. This indicates that BNP enantiomers penetrate deeper into the micellar core of the poly SULL than that of the mono SULL. Varying the temperature resulted in a change in the depth of penetration of BNP into the micellar core of the poly SULL. However, the enantiomers of BNA and BOH always interact preferentially with the N-terminal amino acid of SULL surfactants (both polymer and monomer), independent of the temperatures studied.