Quantum-chemical investigation of interactions in supramolecular systems: cholesterol - bile acids - silica in aqueous solutions

Hypercholesterolemia significantly increases the risk of myocardial infarction associated with COVID-19. Along with pharmacological treatment, the possibility of the excretion of excess cholesterol from an organism by adsorption is also of great interest. The interaction of cholesterol with the surface of partially hydrophobized silica in aqueous solutions of bile acids was investigated by the PM7 method using the COSMO (COnductor-like Screening MOdel) solvation model. The distribution of electrostatic and hydrophobic potentials of molecules and complexes was calculated. The values of free Gibbs energy adsorption of bile acids on the surface of silica correlate with the distribution coefficients in the n-octanol-water system. The energy of interaction of cholesterol with bile acids affects its adsorption on silica. The stronger the bond of cholesterol with the molecules of bile acids, the less it is released from the primary micelles in solution and adsorbed on the surface.

Can the results of quantum refinement be improved with a continuum-solvation model?

Quantum refinement has repeatedly been shown to be a powerful approach to interpret and improve macromolecular crystal structures, allowing for the discrimination between different interpretations of the structure, regarding the protonation states or the nature of bound ligands, for example. In this method, the empirical restraints, used to supplement the crystallographic raw data in standard crystallographic refinement, are replaced by more accurate quantum mechanical (QM) calculations for a small, but interesting, part of the structure. Previous studies have shown that the results of quantum refinement can be improved if the charge of the QM system is reduced by adding neutralizing groups. However, this significantly increases the computation time for the refinement. In this study, we show that a similar improvement can be obtained if the original highly charged QM system is instead immersed in a continuum solvent in the QM calculations. The best results are typically obtained with a high dielectric constant (ɛ). The continuum solvent improves real-space Z values, electron-density difference maps and strain energies, and it normally does not affect the discriminatory power of the calculations between different chemical interpretations of the structure. However, for structures with a low charge in the QM system or with a low crystallographic resolution (>2 Å), no improvement of the structures is seen.

Enthalpies of Adduct Formation between Boron Trifluoride and Selected Organic Bases in Solution: Toward an Accurate Theoretical Entry to Lewis Basicity

The Lewis basicity of selected organic bases, modeled by the enthalpies of adduct formation between gaseous BF3 and the bases in dichloromethane (DCM) solution, is critically examined. Although experimental enthalpies for a large number of molecules have been reported in the literature, it may be desirable to estimate missing or uncertain data for important Lewis bases. We have decided to use high-level ab initio procedures, combined with a polarized continuum solvation model, in which the solvated species are the clusters formed by specific hydrogen bonding of DCM with the Lewis base and the Lewis base/BF3 adduct. This mode of interaction with DCM corresponds to a specific solvation model (SSM). The results actually show that the enthalpy of BF3 adduct formation in DCM solution is clearly influenced by specific interactions, DCM acting as hydrogen-bonding donor (HBD) molecule in two ways: base/DCM and adduct/DCM, confirming that specific solvation is an important contribution to experimentally determined Lewis basicity scales. This analysis allows us to conclude that there are reasons to suspect some gas-phase values to be in error by more than the stated experimental uncertainty. Some experimental values in DCM solution that were uncertain because of identified reasons can be complemented by the computed values.

Enthalpies of Adduct Formation between Boron Trifluoride and Selected Organic Bases in Solution: Toward an Accurate Theoretical Entry to Lewis Basicity

The Lewis basicity of selected organic bases, modeled by the enthalpies of adduct formation between gaseous BF3 and the bases in dichloromethane (DCM) solution, is critically examined. Although experimental enthalpies for a large number of molecules have been reported in the literature, it may be desirable to estimate missing or uncertain data for important Lewis bases. We have decided to use high-level ab initio procedures, combined with a polarized continuum solvation model, in which the solvated species are the clusters formed by specific hydrogen bonding of DCM with the Lewis base and the Lewis base/BF3 adduct. This mode of interaction with DCM corresponds to a specific solvation model (SSM). The results actually show that the enthalpy of BF3 adduct formation in DCM solution is clearly influenced by specific interactions, DCM acting as hydrogen-bonding donor (HBD) molecule in two ways: base/DCM and adduct/DCM, confirming that specific solvation is an important contribution to experimentally determined Lewis basicity scales. This analysis allows us to conclude that there are reasons to suspect some gas-phase values to be in error by more than the stated experimental uncertainty. Some experimental values in DCM solution that were uncertain because of identified reasons can be complemented by the computed values.

Unravelling Constant pH Molecular Dynamics in Oligopeptides with Explicit Solvation Model

An accurate description of the protonation state of amino acids is essential to correctly simulate the conformational space and the mechanisms of action of proteins or other biochemical systems. The pH and the electrochemical environments are decisive factors to define the effective pKa of amino acids and, therefore, the protonation state. However, they are poorly considered in Molecular Dynamics (MD) simulations. To deal with this problem, constant pH Molecular Dynamics (cpHMD) methods have been developed in recent decades, demonstrating a great ability to consider the effective pKa of amino acids within complex structures. Nonetheless, there are very few studies that assess the effect of these approaches in the conformational sampling. In a previous work of our research group, we detected strengths and weaknesses of the discrete cpHMD method implemented in AMBER when simulating capped tripeptides in implicit solvent. Now, we progressed this assessment by including explicit solvation in these peptides. To analyze more in depth the scope of the reported limitations, we also carried out simulations of oligopeptides with distinct positions of the titratable amino acids. Our study showed that the explicit solvation model does not improve the previously noted weaknesses and, furthermore, the separation of the titratable amino acids in oligopeptides can minimize them, thus providing guidelines to improve the conformational sampling in the cpHMD simulations.

Prediction of n-octanol/water partition coefficients and acidity constants (pKa) in the SAMPL7 blind challenge with the IEFPCM-MST model

Within the scope of SAMPL7 challenge for predicting physical properties, the Integral Equation Formalism of the Miertus-Scrocco-Tomasi (IEFPCM/MST) continuum solvation model has been used for the blind prediction of n-octanol/water partition coefficients and acidity constants of a set of 22 and 20 sulfonamide-containing compounds, respectively. The log P and pKa were computed using the B3LPYP/6-31G(d) parametrized version of the IEFPCM/MST model. The performance of our method for partition coefficients yielded a root-mean square error of 1.03 (log P units), placing this method among the most accurate theoretical approaches in the comparison with both globally (rank 8th) and physical (rank 2nd) methods. On the other hand, the deviation between predicted and experimental pKa values was 1.32 log units, obtaining the second best-ranked submission. Though this highlights the reliability of the IEFPCM/MST model for predicting the partitioning and the acid dissociation constant of drug-like compounds compound, the results are discussed to identify potential weaknesses and improve the performance of the method.