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.

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.

Diastereoselective DNA cleavage recognition by Ni(II) x Gly-Gly-His-derived metallopeptides.

Site-selective DNA cleavage by diastereoisomers of Ni(II) x Gly-Gly-His-derived metallopeptides was investigated through high-resolution gel analyses and molecular dynamics simulations. Ni(II) x L-Arg-Gly-His and Ni(II) x D-Arg-Gly-His (and their respective Lys analogues) targeted A/T-rich regions; however, the L-isomers consistently modified a subset of available nucleotides within a given minor groove site, while the D-isomers differed in both their sites of preference and their ability to target individual nucleotides within some sites. In comparison, Ni(II) x L-Pro-Gly-His and Ni(II) x D-Pro-Gly-His were unable to exhibit a similar diastereoselectivity. Simulations of the above systems, along with Ni(II) x Gly-Gly-His, indicated that the stereochemistry of the amino-terminal amino acid produces either an isohelical metallopeptide that associates stably at individual DNA sites (L-Arg or L-Lys) or, with D-Arg and D-Lys, a noncomplementary metallopeptide structure that cannot fully employ its side chain nor amino-terminal amine as positional stabilizing moieties. In contrast, amino-terminal Pro-containing metallopeptides of either stereochemistry, lacking an extended side chain directed toward the minor groove, did not exhibit a similar diastereoselectivity. While the identity and stereochemistry of amino acids located in the amino-terminal peptide position influenced DNA cleavage, metallopeptide diastereoisomers containing L- and D-Arg (or Lys) within the second peptide position did not exhibit diastereoselective DNA cleavage patterns; simulations indicated that a positively charged amino acid in this location alters the interaction of the metallopeptide equatorial plane and the minor groove leading to an interaction similar to Ni(II) x Gly-Gly-His.

Molecular Dynamics Simulations of the Orientation of Ni(II)•Gly-Gly-His and Ni(II)•Arg-Gly-His Metallopeptide-DNA Association.

Ni(II)•Xaa-Gly-His metallopeptides (where Xaa is any α-amino acid) bind selectively to the minor groove of A/T-rich DNA regions as a function of their amino acid composition and chirality. Molecular dynamics simulations were performed to clarify the most likely binding orientations of Ni(II)•Gly-Gly-His and Ni(II)•L-Arg-Gly-His upon association with the B-form oligonucleotide d(CGCGAATTCGCG)2. Upon examination of four possible docking orientations (I-IV), these studies indicated that both metallopeptides favor association with DNA via I, involving insertion of the edge of the metallopeptide containing the amino-terminal N-H and the imidazole pyrrole N-H group of His into the minor groove. These metallopeptide moieties play important roles in this DNA recognition mode by functioning as H-bond donors to minor groove acceptors such as the N3 of adenine or the O2 of thymine located on the floor of the minor groove. The positively charged side chain of L-Arg was found to enhance DNA recognition relative to that exhibited by Ni(II)•Gly-Gly-His through an increased electrostatic interaction, its favorable stereochemistry, and by providing a third point of contact with the minor groove floor. The simulation of orientation I was found to reproduce the experimentally supported DNA-metallopeptide orientation, revealing factors that are important for the further development of DNA-binding ligands.

Ni(II).Arg-Gly-His-DNA interactions: investigation into the basis for minor-groove binding and recognition.

A study of the minor-groove recognition of A/T-rich DNA sites by Ni(II).L-Arg-Gly-His and Ni(II).D-Arg-Gly-His was carried out with a fluorescence-based binding assay, one- and two-dimensional (1D and 2D) NMR methodologies, and molecular simulations. Fluorescence displacement titrations revealed that Ni(II).L-Arg-Gly-His binds to A/T-rich sequences better than the D-Arg diastereomer, while NMR investigations revealed that both metallopeptides bind to the minor groove of an AATT core region as evidenced by an intermolecular nuclear Overhauser effect (NOE) between each metallopeptide His imidazole C4 proton and the C2 proton of adenine. Results from molecular dynamics simulations of these systems were consistent with the experimental data and indicated that the His imidazole N-H, the N-terminal peptide amine, and Arg side chains of each metallopeptide are major determinants of minor-groove recognition by functioning as H-bond donors to the O2 of thymine residues or N3 of adenine residues.

Using stereocartography for predicting efficacy of stereoinduction by chiral catalysts.

A computational method called stereocartography is used to examine regions around chiral catalysts that are most stereoinducing during Diels-Alder reactions. Geometries and atomic charges of catalysts are first generated quantum mechanically. The transition state of the reaction being catalyzed is then computed quantum mechanically and those enantiomeric transition states are used as probes to determine where around the catalyst stereoinduction is optimal. A description of how to treat catalysts with multiple conformations is given. In this article seven catalysts containing a variety of ligand motifs and metals were evaluated. The hypothesis that the region of maximum stereoinduction must be spatially coincident with the site of chemistry for a catalyst to be efficient is upheld.

Chiral recognition of peptide enantiomers by cinchona alkaloid derived chiral selectors: mechanistic investigations by liquid chromatography, NMR spectroscopy, and molecular modeling.

The chiral recognition mechanism of a cinchona alkaloid based chiral selector for N-protected peptide enantiomers was investigated. A chiral stationary phase derived from this selector was employed for liquid chromatographic enantiomer separations. It showed exceptionally high enantiomer discrimination for the (all-R)- and (all-S)-enantiomers of dialanine (alpha = 20), while a pronounced loss of chiral recognition occurred upon the insertion of an additional alanine residue into the peptide backbone. This reduction of enantioselectivity was investigated in great detail by NMR spectroscopy of complexes of the chiral selector and the analyte enantiomers accompanied by molecular modeling studies. Investigation of intramolecular NOEs provided the conformational states of the free and complexed forms of the selector. The analysis of complexation-induced shifts yielded information on intermolecular interactions and allowed us to propose binding models, which were further supported by the observation of intermolecular NOEs, indicating the relative arrangements of selector and analytes. Stochastic molecular dynamics simulations were able to reproduce the chromatographic retention orders and energy differences, as well as the intermolecular NOEs. The computational data were used to evaluate the intermolecular forces responsible for analyte binding. In addition, the relative contributions of the fragments of the chiral selector to the enantioselective binding event were assessed. A spatial arrangement of the chiral selector and the analyte allowing the primary ionic interaction as well as hydrogen bonding and pi-pi-stacking to take place simultaneously was found to be essential to obtain very high enantioselectivities.

Computational studies of chiral catalysts: a comparative molecular field analysis of an asymmetric Diels-Alder reaction with catalysts containing bisoxazoline or phosphinooxazoline ligands.

A QSAR using Comparative Molecular Field Analysis (CoMFA) is developed for a set of 23 catalysts containing bisoxazoline or phosphinooxazoline ligands that are known to induce asymmetry during the Diels-Alder reaction of N-2-alkenoyl-1,3-oxazolidine-2-one with cyclopentadiene. It is shown that extremely high q(2) statistics can be derived by using standard modeling protocols when internal validation alone is done as well as when an external test set is used. From these models it is shown that approximately 70% of the variance in the observed enantiomeric excess can be attributed to the steric field and the remainder of the variance to the electrostatic field. Suggestions about how to improve the performance of inefficient catalysts are given.

Stereocartography: a computational mapping technique that can locate regions of maximum stereoinduction around chiral catalysts.

A hypothesis concerning asymmetric induction by chiral catalysts is posited, tested, and found to be valid. The hypothesis states that chiral catalysts that are efficient at inducing asymmetry will have their region of maximum stereoinduction spatially congruent with the site of chemistry but inefficient catalysts will not. A simple mapping strategy (stereocartography) is used to assess where the region of maximum stereoinduction is located around a given catalyst. The protocol compares interaction energies between mirror image probes at each point in space around the catalyst being considered. The probes are models of the actual transition states of the reaction being catalyzed by a particular catalyst. The hypothesis was tested on three Diels-Alder reactions. Seventeen of the eighteen catalysts conform to the hypothesis. The idea of using this as a catalyst design tool is presented.

Elucidation of the chiral recognition mechanism of cinchona alkaloid carbamate-type receptors for 3,5-dinitrobenzoyl amino acids.

A cinchona alkaloid having extraordinary chiral discriminatory powers (alpha = 32.6 for dinitrobenzoyl leucine) is developed as a chiral stationary phase (CSP) for chromatography. An explanation of how chiral discrimination takes place is presented. Using a soluble analogue of the CSP, we found that NMR spectrometry indicates that 1:1 complexes exist for both optical isomers interacting with the CSP, that the free base form of the CSP exists in an open/closed ratio of 35/65 but that the protonated, bound-state form is exclusively in the anti-open conformation, and that significant intermolecular NOEs exist for the more stable diastereomeric complex but not for the less stable complex. Stochastic molecular dynamics simulations were carried out in solvents of low and high dielectric. The chromatographic retention orders and free energy differences of analyte binding to CSP were reproduced computationally as were the observed intra- and intermolecular NOEs. Data from the simulation were used to evaluate the intermolecular forces responsible for analyte binding as well as to discern fragments of the CSP doing most of the work of holding the complexes together. The enantiodifferentiating forces and the parts of the CSP most responsible for chiral discrimination are described. Moments of distributions of key dihedral angles and distances between centroids were used to assess the relative rigidity of the competing diastereomeric complexes. Simultaneous multiple-contact ion-pairing, hydrogen bonding, and pi-stacking are possible for the longer retained enantiomer only. An X-ray crystallographic study of the more stable complex confirms the conclusions derived from chromatography, NMR spectroscopy, and molecular modeling.

Ligand distortion modes leading to increased chirality content of Katsuki-Jacobsen catalysts.

The "chirality content" of Katsuki-Jacobsen epoxidation catalysts are computed with the Avnir continuous chirality measure (CCM). An assessment of Mn(salen) molecules from the Cambridge Structural Database shows there exist some variation in CCM and the chirality content for several triplet state complexes of these catalysts purported in the literature to be the active species show even larger CCM values. Several deformation modes were analyzed to examine how chirality content changes as catalyst distortion is induced. The deformations studied include in-plane deformations, cup-shaped puckering, ligand twisting motions, and step-like deformations. Some distortions lead to increases of chirality while others lead to a decrease in chirality content. The most influential distortion modes that can be used for ligand design are twisting and step induction.

The Principle of Maximum Chiral Discrimination: Chiral Recognition in Permethyl-beta-cyclodextrin.

Five guest molecules, isomenthone, pulegone, 1-fluoro-1-phenylethane, 1-phenylethanol, and 2-methylbutanoic acid, binding to permethyl-beta-cyclodextrin, a chiral host molecule, have been simulated by molecular dynamics techniques. From the simulations we find the preferred binding site to be the interior of the macrocyclic cavity. A new technique was used for locating the host's most enantiodiscriminating domain, which was also found to be inside the macrocyclic cavity. It is concluded that this particular host molecule displays its enhanced chiral discriminating capacity because of this spatial coincidence. Also evaluated in this paper are the types and magnitudes of intermolecular forces responsible for diastereomeric complexation and chiral discrimination; in both cases the short-range dispersion forces dominate. This study illustrates the "principle of maximum chiral recognition", the idea that maximum chiral recognition can be achieved by maintaining a spatial congruence between the host's domain of greatest enantiodifferentiation with the guest's preferred binding site.