Taste for Chiral Guests: Investigating the Stereoselective Binding of Peptides to β-Cyclodextrins

Abstract

Obtaining compounds of diastereomeric purity is extremely important in the field of biological and pharmaceutical industry, where amino acids and peptides are widely employed. In this work, we theoretically investigate the possibility of chiral separation of peptides by β-cyclodextrins (β-CDs), providing a description of the associated interaction mechanisms by means of molecular dynamics (MD) simulations. The formation of host/guest complexes by including a model peptide in the macrocycle cavity is analyzed and discussed. We consider the terminally blocked phenylalanine dipeptide (Ace-Phe-Nme), in the L- and D-configurations, to be involved in the host/guest recognition process. The CD-peptide free energies of binding for the two enantiomers are evaluated through a combined approach that assumes: (1) extracting a set of independent molecular structures from the MD simulation, (2) evaluating the interaction energies for the host/guest complexes by hybrid quantum mechanics/molecular mechanics (QM/MM) calculations carried out on each structure, for which we also compute, (3) the solvation energies through the Poisson-Boltzmann surface area method. We find that chiral discrimination by the CD macrocycle is of the order of 1 kcal/mol, which is comparable to experimental data for similar systems. According to our results, the Ace-(D)Phe-Nme isomer leads to a more stable complex with a β-CD compared to the Ace-(L)Phe-Nme isomer. Nevertheless, we show that the chiral selectivity of β-CDs may strongly depend on the secondary structure of larger peptides. Although the free energy differences are relatively small, the predicted selectivities can be rationalized in terms of host/guest hydrogen bonds and hydration effects. Indeed, the two enantiomers display different interaction modes with the cyclodextrin macrocavity and different mobility within the cavity. This finding suggests a new interpretation for the interactions that play a key role in chiral recognition, which may be exploited to design more efficient and selective chiral separations of peptides.

Chiral Recognition of d-Tryptophan by Confining High-Energy Water Molecules Inside the Cavity of Copper-Modified β-Cyclodextrin

“…In this way, the -NH 2 at the chiral center of D-Trp and the high-energy water molecules inside the cavity form strong intermolecular H-bonds due to steric reasons, giving the Cu 2 -β-CD higher affinity to D-Trp. This work is also the fisrt example verifying the theory proposed by Altarsha et al, 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 5 they stated that β-CD has a higher affinity to D-isomers entered into the cavity from the narrower opening based on the investigations of molecular dynamic (MD) simulations. 30 Furthermore, the Cu 2 -β-CD can be self-assembled onto P-L-Glu by either H-bonds or electrostatic interactions ( Figure 1). Interestingly, the Cu 2 -β-CD attached to P-L-Glu via H-bonds exhibited greater capability of recognition for Trp isomers compared to that attached via electrostatic interactions, which was mainly attributed to the different configurations of the Cu 2 -β-CD cavity by the two different self-assembly modes.…”

Tetrel, chalcogen, and CH⋅⋅O hydrogen bonds in complexes pairing carbonyl-containing molecules with 1, 2, and 3 molecules of CO2

“…[11][12][13][14][15][16] Other efforts have added to understanding the interactions of CO 2 with various solutes, especially those containing carbonyl functional groups or aromatic systems and other heteroatoms as nitrogen, sulfur, or halogens in their compositions. [17][18][19][20][21][22][23][24][25][26][27][28] These works have added to our understanding by providing a clear definition of the conformational landscape in systems in which CO 2 acts as both electron acceptor and donor in noncovalent complexes with different solutes and in the presence of a variety of heteroatoms in their compositions, which offer many peculiarities in their structures.…”

Fast, metadynamics‐based method for prediction of the stereochemistry‐dependent relative free energies of ligand–receptor interactions

“…Computations of based on MD simulations have a long history that can be traced back to the 1980s . Free‐energy calculations give insight into analysis of the structural features, and the stereoselective mechanism of physical and chemical processes, for example, reaction pathway, stereoselective catalysis, hydroxylation, selective complexation, polymerization, and ligand binding …”