Cavity Closure Dynamics of Peracetylated β-Cyclodextrins in Supercritical Carbon Dioxide

Structural properties of peracetylated β-cyclodextrin in supercritical carbon dioxide were investigated by means of molecular dynamics simulations. The study indicated a strong reduction of the cavity accessibility to guest molecules, compared to native β-cyclodextrin in water. Indeed, the cavity is self-closed during the largest part of the simulation, which agrees well with suggestions made on the basis on high-pressure NMR experiments. Self-closure happens because one glucose unit undergoes a main conformational change (from chair to skew) that brings one of the acetyl groups in the wide rim of the cyclodextrin to the cavity interior. This arrangement turns out to be quite favorable, persisting for several nanoseconds. In addition to the wide rim self-closure, a narrow rim self-closure may also occur, though it is less likely and exhibits short duration (<1 ns). Therefore, the number of solvent molecules reaching the cavity interior is much smaller than that found in the case of native β-cyclodextrin in water after correction to account for different molar densities. These findings support the weak tendency of the macromolecule to form host–guest complexes in this nonconventional medium, as reported by some experiments. Finally, Lewis acid/base interactions between the acetyl carbonyl groups and the solvent CO₂ molecules were analyzed through ab initio calculations that revealed the existence of a quite favorable four-member ring structure not yet reported. The ensemble of these results can contribute to establish general thermodynamic principles controlling the formation of inclusion complexes in supercritical CO₂, where the hydrophilicity/hydrophobicity balance is not applicable

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

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

Hydration Effect on Amide I Infrared Bands in Water: An Interpretation Based on an Interaction Energy Decomposition Scheme

The sensitivity of some infrared bands to the local environment can be exploited to shed light on the structure and the dynamics of biological systems. In particular, the amide I band, which is specifically related to vibrations within the peptide bonds, can give information on the ternary structure of proteins, and can be used as a probe of energy transfer. In this work, we propose a model to quantitatively interpret the frequency shift on the amide I band of a model peptide induced by the formation of hydrogen bonds in the first solvation shell. This method allows us to analyze to what extent the electrostatic interaction, electronic polarization and charge transfer affect the position of the amide I band. The impact of the anharmoniticy of the pontential energy surface on the hydration induced shift is elucidated as well

Cost-Effective Method for Free-Energy Minimization in Complex Systems with Elaborated Ab Initio Potentials

We describe a method to locate stationary points in the free-energy hypersurface of complex molecular systems using high-level correlated <i>ab initio</i> potentials. In this work, we assume a combined QM/MM description of the system although generalization to full <i>ab initio</i> potentials or other theoretical schemes is straightforward. The free-energy gradient (FEG) is obtained as the mean force acting on relevant nuclei using a dual level strategy. First, a statistical simulation is carried out using an appropriate, low-level quantum mechanical force-field. Free-energy perturbation (FEP) theory is then used to obtain the free-energy derivatives for the target, high-level quantum mechanical force-field. We show that this composite FEG-FEP approach is able to reproduce the results of a standard free-energy minimization procedure with high accuracy, while simultaneously allowing for a drastic reduction of both computational and wall-clock time. The method has been applied to study the structure of the water molecule in liquid water at the QCISD/aug-cc-pVTZ level of theory, using the sampling from QM/MM molecular dynamics simulations at the B3LYP/6-311+G­(d,p) level. The obtained values for the geometrical parameters and for the dipole moment of the water molecule are within the experimental error, and they also display an excellent agreement when compared to other theoretical estimations. The developed methodology represents therefore an important step toward the accurate determination of the mechanism, kinetics, and thermodynamic properties of processes in solution, in enzymes, and in other disordered chemical systems using state-of-the-art <i>ab initio</i> potentials

Intramolecular Interactions versus Hydration Effects on <i>p</i>‑Guanidinoethyl-phenol Structure and p<i>K</i>_a Values

We analyze the structure, hydration, and p<i>K</i>_a values of <i>p</i>-guanidinoethyl-phenol through a combined experimental and theoretical study. These issues are relevant to understand the mechanism of action of the tetrameric form, the antibacterial compound tetra-<i>p</i>-guanidinoethyl-calix­[4]­arene (Cx1). The investigated system can also be useful to model other pharmaceutical drugs bearing a guanidine function in the vicinity of an ionizable group and the effect of arginine on the p<i>K</i>_a of vicinal ionizable residues (in particular tyrosine) in peptides. The <i>p</i>-guanidinoethyl-phenol monomer (mCx1) has two ionizable groups. One important particularity of this system is that it exhibits high molecular flexibility that potentially leads to enhanced stabilization in folded structures by direct, strong Coulombic interactions between the ionizable groups. The first p<i>K</i>_a corresponding to ionization of the −OH group has experimentally been shown to be only slightly different from usual values in substituted phenols. However, because of short-range Coulombic interactions, the role of intramolecular interactions and solvation effects on the acidities of this compound is expected to be important and it has been analyzed here on the basis of theoretical calculations. We use a discrete-continuum solvation model together with quantum-mechanical calculations at the B3LYP level of theory and the extended 6-311+G­(2df,2p) basis set. Both intra- and intermolecular effects are very large (∼70 kcal/mol) but exhibit an almost perfect compensation, thus explaining that the actual p<i>K</i>_a of mCx1 is close to free phenol. The same compensation of environmental effects applies to the second p<i>K</i>_a that concerns the guanidinium group. Such a p<i>K</i>_a could not be determined experimentally with standard titration techniques and in fact the theoretical study predicts a value of 14.2, that is, one unit above the p<i>K</i>_a of the parent ethyl-guanidinium molecule

Atmospheric Significance of Water Clusters and Ozone–Water Complexes

Ozone–water complexes O₃···(H₂O)_<i>n</i> (<i>n</i> = 1–4) have been theoretically investigated using QCISD and CCSD­(T) methods along with the 6-311G­(2df,2p), 6-311+G­(2df,2p), aug-cc-pVDZ, aug-cc-pVTZ, and aug-cc-pVQZ basis sets and extrapolation to CBS limit. For comparison, water clusters (H₂O)_<i>n</i> (<i>n</i> = 1–4) have also been studied at the same level of theory. The ozone–water complexes are held together by a combination of weak specific hydrogen-bonding and van der Waals interactions. Surprisingly, the hydrogen-bonded complexes are not necessarily the most stable ones. In particular, in the most stable 1:1 complex structure the main stabilizing factors come from van der Waals interactions. The high accuracy of the calculated binding energies provides a reliable basis to discuss the abundance of these clusters in the atmosphere. We predict concentrations up to 9.24 × 10¹⁵, 3.91 × 10¹⁴, and 2.02 × 19¹⁴ molecules·cm^–3 for water dimer, trimer, and tetramer in very hot and humid conditions and that the concentrations of these clusters would remain significant up to 10 km of altitude in the Earth’s atmosphere. The concentration of O₃···H₂O is predicted to be between 1 and 2 orders of magnitude higher than previous estimation from the literature: up to 5.74 × 10⁸ molecules·cm^–3 in very hot and humid conditions at ground level and up to 1.56 × 10⁷ molecules·cm^–3 at 10 km of altitude of the Earth’s atmosphere. The concentrations of the other ozone–water clusters, O₃··(H₂O)₂, O₃···(H₂O)₃, and O₃···(H₂O)₄, are predicted to be very small or even negligible in the atmosphere