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The structure, tautomeric preferences, base-pairing ability, stacking interactions and HOMO-LUMO gaps of the naphtho-homologated DNA bases are studied using theoretical techniques. The bases have structures similar to the benzo-fused predecessors and show a tautomeric preference to naphtho-thymine and naphtho-adenine resulting in formation of hydrogen-bonded dimers.

A perturbation approach based on the generalized molecular interaction potential with polarization (GMIP(sub p)) was developed for combined quantum mechanical and molecular molecular mechanical (QM/MM) simulations of solutions. It shows that the use of the GMIP(sub p) gives an accurate representation of solute-solvent interactions.

The influence of pentahydrated Mg(super 2+) cation binding on the Hoogsteen G-G.C triplet motif is investigated. The studies show that the cation-induced polarization plays a significant contribution to the stabilization of the triplet.

Hydrogen bonds (H-bonds) determine the three-dimensional structures of biomacromolecule and therefore one of the key interactions in molecular biology. Harmonic vibrational analysis performed at the correlated MP2 level reveals two H-bonds of N-H...N and N-H...O types in the adenine...uracil Watson-Crick (AU WC) base pairs while no support is given to existence of the third bond, either C-H...O H-bond or improper blue-shifting H-bond.

Research was conducted to examine the tautomerism of the N-1-methylated derivatives of thymine, uracil and 5-bromouracil to investigate its implications in the mutagenicity of 5-bromouridine. State-of-the-art ab initio quantum mechanical calculations were utilized to determine the tautomeric preference in the gas phase. Results indicate that the enol tautomers of uracil, thymine and 5-bromouracil are intrinsincally unstable in the gas phase.

A high-level ab initio method was used to study the three-dimensional potential energy surfaces with two independent variables corresponding to rotations around the [alpha] and [gamma] backbone torsions. The comparison of the ab initio data with ff99 potential energy surface showed an incorrect ff99 force-field description in the region where the [gamma] torsion is in the trans conformation.

A study is conducted to define the cavity between the solute and solvent for predicting hydration free energies of univalent ions. The method used provides with a minimum number of fitted parameters, reasonable estimates within the experimental error of the hydration free energy of ions and has the capability to reproduce solvation in water of both small and large ions.

A theoretical investigation of the influence of divalent metal cation binding on nucleic base pairing is presented. The study concluded that a metal cation binding to nucleotides and base pairs has pronounced effects on structural, energetic, and electronic properties of the interacting bases.

Depending on the chemical scaffold, a bioactive species could reflect the interplay between ionization and tautomerism, which is often complicated by the possibility of populating different conformational states, in the case of flexible ligands. In this context, theoretical methods can be valuable to discern the role of these factors, as shown here for β-enamino esters of 1,2,3,6-tetrahydroazocino-fused ring systems, some of which had proven to be suitable scaffolds for designing novel acetylcholinesterase inhibitors. The compounds investigated herein form two clusters with distinctive experimental p K a values (i.e., α,β-diesters and β-esters ranging within 6.1-7.3 and 8.2-9.0 p K a intervals, respectively), which implies a drastic difference in the most populated species at physiological conditions. While chemoinformatic tools did not provide a consistent description of the actual p K a values, the theoretical analysis performed for the protonated and neutral species of these compounds revealed a marked change in the tautomeric preference of the tetrahydroazocine moiety upon (de)protonation. Excellent agreement between the calculated and experimental p K a values was found when the tautomeric preference of the protonated and neutral species was considered. Overall, this study highlights the potential use of high-level computational methods to disclose the mutual influence between ionization, tautomerism, and conformational preferences in multifunctional (bio)organic compounds.

Predicting the conformational preferences of flexible compounds is a challenging problem in drug design, where the recognition between ligand and receptor is affected by the ability of the interacting partners to adopt a favorable conformation for the binding. To explore the conformational space of flexible ligands and to obtain the relative free energy of the conformation wells, we have recently reported a multilevel computational strategy that relies on the predominant-state approximation-where the conformational space is partitioned into distinct conformational wells-and combines a low-level method for sampling the conformational minima and high-level ab initio calculations for estimating their relative stability. In this study, we assess the performance of the multilevel strategy for predicting the conformational preferences of a series of structurally related phenylethylamines and streptomycin in aqueous solution. The charged nature of these compounds and the chemical complexity of streptomycin make them a challenging test for the multilevel approach. Furthermore, we explore the suitability of using a molecular mechanics approach as a source of approximate ensembles in the first stage of the multilevel strategy. The results support the reliability of the multilevel approach for obtaining an accurate conformational ensemble of small (bio)organic molecules in aqueous solution.

The accuracy and performance of implicit solvent methods for solvation free energy calculations were assessed on a set of 20 neutral drug molecules. Molecular dynamics (MD) provided ensembles of conformations in water and water-saturated octanol. The solvation free energies were calculated by popular implicit solvent models based on quantum mechanical (QM) electronic densities (COSMO-RS, MST, SMD) as well as on molecular mechanical (MM) point-charge models (GB, PB). The performance of the implicit models was tested by a comparison with experimental water-octanol transfer free energies (ΔG(ow)) by using single- and multiconformation approaches. MD simulations revealed difficulties in a priori estimation of the flexibility features of the solutes from simple structural descriptors, such as the number of rotatable bonds. An increasing accuracy of the calculated ΔG(ow) was observed in the following order: GB1 ~ PB < GB7 ≪ MST < SMD ~ COSMO-RS with a clear distinction identified between MM- and QM-based models, although for the set excluding three largest molecules, the differences among COSMO-RS, MST, and SMD were negligible. It was shown that the single-conformation approach applied to crystal geometries provides a rather accurate estimate of ΔG(ow) for rigid molecules yet fails completely for the flexible ones. The multiconformation approaches improved the performance, but only when the deformation contribution was ignored. It was revealed that for large-scale calculations on small molecules a recent GB model, GB7, provided a reasonable accuracy/speed ratio. In conclusion, the study contributes to the understanding of solvation free energy calculations for physical and medicinal chemistry applications.

Protoglobin is the first globin found in Archaea. Its biological role is still unknown, although this protein can bind O(2), CO, and NO reversibly in vitro. The X-ray structure of Methanosarcina acetivorans protoglobin (MaPgb) has shown that access of ligands to the heme, which is completely buried within the protein matrix, can be granted by two apolar tunnels, which are mainly defined by helices G and B (tunnel 1), and helices B and E (tunnel 2). Here we analyze the structural and dynamical behavior of MaPgb through molecular dynamics and computational techniques aimed at shedding light on distinctive features of ligand migration through the tunnels that may be linked to functionality. While tunnel 2 is found to be accessible to diatomic ligands in both deoxygenated and oxygenated forms of the protein, the accessibility of tunnel 1 is controlled through the synergistic effect of both the protein dimeric state and the presence of the heme-bound ligand. Thus, dimerization mainly affects the spatial arrangement of helix G, which influences the shape of tunnel 1. Ligand accessibility through this tunnel is regulated by Phe(145)G8, which can adopt open and closed conformations. Noteworthy, the ratio between open and closed states is modulated by protein dimerization and more strikingly by ligand binding. In particular, sensing of the ligand is mediated by Phe(93)E11, and the steric hindrance between Phe(93)E11 and the heme-bound ligand alters the structural and dynamical behavior of helices B and E, which facilitates opening of tunnel 1. This functional mechanism provides a basis to understand the finding that ligation favors fast rebinding from ligand binding kinetic to MaPgb. Finally, it also suggests that MaPgb might be physiologically involved in a ligand-controlled bimolecular chemical process., (© 2011 American Chemical Society)