Rodrigo Martínez

Reaction mechanisms and rate constants of the acylation reaction of the hepatitis C virus (HCV) NS3/NS4A serine protease with the NS4B/5A natural substrate were studied using SCC-DFTB/MM (self-consistent charge density functional tight binding/molecular mechanics) and EA-VTST/MT (ensemble-averaged variational transition state theory/multidimensional tunneling) methods, considering the isotope effect (H/D). This reaction is crucial in the HCV life cycle. The reaction follows an essentially concerted mechanism. Although two elementary steps are involved, no intermediate step has been found between them. Thus, the proposed general two-step serine protease acylation mechanism, which includes a tetrahedral intermediate, does not occur here. This finding aligns with our studies on another natural substrate (NS5A/5B), indicating a greater variety in mechanism than previously expected. Tunneling and recrossing play an intermediate role; the activation free energy barriers are in good agreement with the experimental value, and the kinetic isotope effect (k(H)/k(D)) is somewhat larger than one (1.3). The rate constant value is not reproduced due to the exponential dependence of the rate constant on the activation free energy.

The popular sweetener, aspartame, is an agonist of the tongue's sweet taste receptor. How water molecules affect its conformation or which aspartame atoms are more prone to interact with solvent are helpful questions to understand its activity in different environments. Here, the combination of IR-UV spectroscopic techniques with computational simulations has been successfully applied to characterize aspartamewater(0-2) clusters, showing that the addition of water molecules simplifies the conformational panorama of aspartame, favoring the formation of folded structures by interaction with the polar part of the molecule.

Election of cytosine, guanine, thymine and adenine as the components of the information biopolymers was a complex process, influenced by several factors. Among them, the intermolecular interactions may have played a determinant role. Thus, a deep understanding of the intermolecular interactions between nucleobases and other prebiotic molecules may help understand the first instants of chemical evolution. Following this hypothesis, we present here a combined spectroscopic and computational study of theobromine₂-adenine and thebromine-adenine₂ trimers. While adenine is a nucleobase, theobromine was probably part of the prebiotic chemistry. The trimers were formed in jets and probed by a combination of UV and IR spectroscopic techniques. The spectra were interpreted on the light of the predictions obtained using density functional methods. The results suggest the existence of a subtle balance between formation of hydrogen bonds and p-p interactions. Thus, while theobromine₂-adenine tends to form complex in stacked structures, theobromine-adenine₂ prefers formation of planar structures, maximizing the interaction by hydrogen bonds. The small energy difference between planar and stacked structures, highlights the importance of accurately model the dispersion forces in the functionals to produce reliable predictions.

Epigenetic marks are modest chemical modifications on DNA and histone proteins that regulate the activation or silencing of genes through modulation of the intermolecular interactions between the DNA strands and the protein machinery. The process is complex and not always well understood. One of the systems studied in greater detail is the epigenetic mark on H3K9: lysine 9 of histone 3. The degree of methylation or acetylation of this histone is linked to silencing or activation of the corresponding gene, but it is not clear which effect each mark has in gene expression. We shed light on this particular methylation process by using density functional theory (DFT) calculations. First, we built a model consisting of a DNA double strand containing three base pairs and a sequence of three amino acids of the histone's tail. Then, we computed the modulation introduced into the intermolecular interactions by each epigenetic modification: from mono‐ to trimethylation and acetylation. The calculations show that whereas acetylation and trimethylation result in a reduction of the DNA‐peptide interaction; non‐, mono‐, and dimethylation increase the intermolecular interactions. Such observations compare well with the findings reported in the literature, and highlight the correlation between the balance of intermolecular forces and biological properties, simultaneously advancing quantum‐mechanical studies of large biochemical systems at molecular level through the use of DFT methods.

Weaker intermolecular forces expand the isomerization alternatives for molecular aggregation, as observed for the prototype models of the aniline trimer (An₃) and the monohydrated aniline dimer (An₂‐W) when compared to the phenol trimer. In this experiment the aniline clusters were generated in a jet‐cooled expansion and probed using broadband (chirped‐pulsed) microwave spectroscopy. Three isomers of the aniline trimer and two isomers of the hydrated dimer were detected and characterized in the rotational spectrum. In the homotrimer the weak N−H⋅⋅⋅N hydrogen bonds are assisted by subtle combinations of N−H⋅⋅⋅π and C−H⋅⋅⋅π interactions, producing several competing low‐lying ring species in the gas phase. One of the aniline trimers is a symmetric top, topologically equivalent to the only observed phenol trimer. Conversely, addition of a water molecule to the aniline dimer introduces a leading O−H⋅⋅⋅N interaction, making water to behave as dominant hydrogen‐bond pivot between the two aniline molecules. This combination of weak intermolecular interactions critically tests the performance of dispersion‐corrected or parametrized density‐functional methods. Evaluation of the B3LYP‐D3(BJ) and M06‐2X methods revealed deficiencies of the Truhlar functional to reproduce the experimental rotational data.

Weaker intermolecular forces expand the isomerization alternatives for molecular aggregation, as observed for the prototype models of the aniline trimer (An₃) and the monohydrated aniline dimer (An₂‐W) when compared to the phenol trimer. In this experiment the aniline clusters were generated in a jet‐cooled expansion and probed using broadband (chirped‐pulsed) microwave spectroscopy. Three isomers of the aniline trimer and two isomers of the hydrated dimer were detected and characterized in the rotational spectrum. In the homotrimer the weak N−H⋅⋅⋅N hydrogen bonds are assisted by subtle combinations of N−H⋅⋅⋅π and C−H⋅⋅⋅π interactions, producing several competing low‐lying ring species in the gas phase. One of the aniline trimers is a symmetric top, topologically equivalent to the only observed phenol trimer. Conversely, addition of a water molecule to the aniline dimer introduces a leading O−H⋅⋅⋅N interaction, making water to behave as dominant hydrogen‐bond pivot between the two aniline molecules. This combination of weak intermolecular interactions critically tests the performance of dispersion‐corrected or parametrized density‐functional methods. Evaluation of the B3LYP‐D3(BJ) and M06‐2X methods revealed deficiencies of the Truhlar functional to reproduce the experimental rotational data.

The four bases of DNA constitute what is known as the “alphabet of life”.

The dynamics of the title reaction was studied using mainly the quasiclassical trajectory (QCT) method on the ground 1²A′′ (OH⁺ channel) and first excited 1²A′ (OH channel) potential energy surfaces (PESs) employing ab initio analytical representations of the PESs developed by us.