Molecular Simulation of the Separation of Isoleucine Enantiomers by β-Cyclodextrin

Abstract

Molecular mechanics and dynamics simulations were carried out to study the capacity of isoleucine enantiomers to form inclusion complexes with β–cyclodextrin, and to be discriminated by this chiral compound, in vacuo and with different solvents. Solvents were characterized not only by the value of dielectric constant ε in the Coulombic interaction energy, but also by the neutral and zwitterion configurations of isoleucine. Whereas the discrimination between the enantiomers for ε ≤ 2 is due to the electrostatic contribution, these differences are mainly due to the Lennard-Jones potential for ε > 2. The most enantioselective regions are located near the cavity walls, independently of the solvent. D-Ile is more stable than L-Ile in broader regions in vacuo, but L-Ile presents more stable locations with water. Isoleucine can form inclusion complexes with β–cyclodextrin in vacuo and with different solvents. Two probable configurations are deduced from the molecular dynamics simulation, in which the guest is always inside the cavity and with the carboxylic end of the amino acid oriented towards either rim of β–CD. In the simulation, the enantiomers preferentially occupy regions with greater chiral discrimination. The first eluted enantiomer in vacuo and with different solvents is L-Ile, independently of the solvent polarity.

Molecular Simulation of the Separation of Some Amino Acid Enantiomers by β-Cyclodextrin in Gas-Phase

“…Alanine and Val remain in zones that are not so enantioselective, whereas Leu and Ile frequent regions with great chiral discrimination. Since Leu and Ile are unable to rotate freely inside the cavity, their evolution through the simulation depends on their initial orientation and which rim of CD they approach from Alvira ( 2019 ). The greater residence times for Leu and Ile correspond to trajectories with initial dispositions of the amino acid near the wide rim and with the amino end pointing to β-CD.…”

“…The minimum energy complex structure is determined by MM simulation, and it is considered an inclusion complex if the guest (amino acid) is totally or partially inside the host (β-CD). The molecular configuration of β-CD and atomic charges are taken from the literature (Kinglert and Rihs, 1991 ), but the atomic coordinates of amino acids are calculated by the Hartree-Fock method, as previously for Ile (Alvira, 2019 ). The 6-31G ** basis set implemented in the MOLPRO package (Werner et al, 2012a , b , MOLPRO) is used to determine the amino acid structures, instead of the force field model proposed by Weiner et al ( 1984 , 1986 ) for nucleic acids and proteins.…”

“…In our previous studies with amino acids, we tested different models to calculate the initial dispositions of enantiomers based on energetic, numerical or geometrical criteria (Alvira, 2017b ). The method applied in the present study minimizes the differences in the van der Waals energy and average atomic distances between the enantiomers, as we already adopted in our more recent research with Ile (Alvira, 2019 ). The smallest differences in both energy and atomic positions are those of Val (average values 3.8 × 10 −6 kcal/mol, 0.11 Å), very similar to Ile (1.6 × 10 −5 kcal/mol, 0.14 Å), then Leu (2.8 × 10 −5 kcal/mol, 0.40 Å).…”

“…Twenty trajectories are calculated in the simulation, with initial enantiomer dispositions outside the cavity facing the rims of β-CD, since when the guest starts from positions near the cavity walls it does not enter the cavity but moves away. We consider different guest orientations parallel to the rims and pointing toward the wide or narrow rim of β-CD (Alvira, 2019 ), doing the same for all the amino acids to make the results comparable. The simulation time for each trajectory is 5 ns with a step of 1 fs, and the energies and guest dispositions were registered every 100 steps.…”

“…This diverged from the results proposed by Ramirez et al ( 2000 ) and Lee et al ( 2017 ). The most useful modification in the molecular simulation applied to Ile (Alvira, 2019 ) was the ab initio method used to determine the amino acid configurations, instead of the force field proposed by Weiner et al for the molecular mechanics simulation of nucleic acids and proteins (Weiner et al, 1984 , 1986 ), used in our earlier studies (Alvira, 2013 , 2015 , 2017a ). The aim of the present work was to apply the model proposed for Ile to theoretically examine the interaction between Ala, Val, and Leu with β-CD in vacuo.…”