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Carboxy-biotin serves as a coenzyme in certain carboxylases, exhibiting the remarkable capability to transfer a carboxy group to specific substrates. This process is made possible by the presence of biotin, a unique molecule that consists of a sulfur-containing tetrahydrothiophene ring fused to a ureido group. It is covalently attached to the enzyme via a flexible linker, allowing for its functionality. Biotin-dependent carboxylases consist of two distinct domains. The first domain (BC) facilitates biotin carboxylation by utilizing ATP, while the second domain (CT) transfers CO2to the substrate. The process of ATP-dependent carboxylation using bicarbonate in the biotin carboxylase domain (BC) is well-known. However, the precise mechanism by which CO2is released in the carboxyltransferase domain (CT) is still not fully understood. We employed advanced computational chemistry methods to investigate the decarboxylation process of carboxy-biotin in various molecular environments and different protonation states. Regardless of the polarity of the molecular surroundings, decarboxylation only occurs spontaneously in the protonated form. To determine the protonation state of biotin in different environments, we established an accurate computational chemistry method for calculating the pKavalue of carboxy-biotin, reaching sub-kcal/mol accuracy. Based on our findings, nonpolar environments, such as the active site of the carboxyltransferase domain, have the ability to cause the spontaneous release of CO2from carboxy-biotin. The CO2release takes place spontaneously from protonated carboxy-biotin, promoting the carboxylation of substrates.

Binding affinity prediction by means of computer simulation has been increasingly incorporated in drug discovery projects. Its wide application, however, is limited by the prediction accuracy of the free energy calculations. The main error sources are force fields used to describe molecular interactions and incomplete sampling of the configurational space. Organic host–guest systems have been used to address force field quality because they share similar interactions found in ligands and receptors, and their rigidity facilitates configurational sampling. Here, we test the binding free energy prediction accuracy for 14 guests with an aromatic or adamantane core and the CB7 host using molecular electron density derived nonbonded force field parameters. We developed a computational workflow written in Python to derive atomic charges and Lennard-Jones parameters with the Minimal Basis Iterative Stockholder method using the polarized electron density of several configurations of each guest in the bound and unbound states. The resulting nonbonded force field parameters improve binding affinity prediction, especially for guests with an adamantane core in which repulsive exchange and dispersion interactions to the host dominate.

The dependence of the relative energies of 116 diphosphene and diphosphinylidene compounds on the modification of their structures is studied theoretically. Optimized geometries and relative energies are reported for all structures. With the purpose of investigating the effects of various substituents on the parent PPH2and HPPH molecules, isodesmic reaction energies were obtained for single and double substitution. In the case of the substitution of both H atoms by lithoxy (OLi) or ONa groups is the diphosphinylidene type structure found to be lower in energy. For the lithoxy group, the energy difference amounts to 33 kcal/mol at CCSD(T) cc-pVTZ level of theory. This result is explained through the natural population analyses, where a very favorable Coulombic attraction is found in the OLi substituted diphosphinylidene structure. The order of the effectiveness of the substituents in lowering the relative energy of the diphosphinylidene structure is OLi > ONa > OH > OSiH3> OCH3> OPh > NH2> N(CH3)2> F > ONH2> OBH2> CH3> OOH > Ph > BF2> PH2> SiH3> SH > HCO > Cl > CF3> Br > SiF3> NF2> NO2> CCH > OF > CN. Natural bond orbital (NBO) analysis explains other qualitative bonding features, for example, phosphorus–phosphorus bond orders as large as 2.5 for R2PP structures and as small as 1.6 for RPPR structures.

The knowledge of the binding energy of molecules on astrophysically relevant ices can help to obtain an estimate of the desorption rate, i.e. the molecules residence time on the surface. This represents an important parameter for astrochemical models, and it is crucial to determine the chemical fate of interstellar complex organic molecules formed on the surface of dust grains and observed in the densest regions of the interstellar medium through rich rotational lines. In this work, we propose a new robust procedure to study the interaction of atoms and molecules with interstellar ices, based on ab initiomolecular dynamics and density functional theory, validated by high-level ab initiomethods at a CCSD(T)/CBS level. We have applied this procedure to a simple but astronomically relevant molecule, hydrogen fluoride (HF), a promising tracer of the molecular content of galaxies. In total we found 13 unique equilibrium structures of HF binding to small water clusters of up to 4 molecules, with binding energies ranging from 1208 K to 7162 K (2.40 to 14.23 kcal mol−1). We computed a 22-molecules model of amorphous solid water (ASW) surface using ab initiomolecular dynamics simulations and carried out a systematic analysis of the binding sites of HF, in terms of binding modes and binding energies. Considering 10 different water clusters configurations, we found a binding energy distribution with an average value of 5313±74K, and a dispersion of 921±115K (10.56±0.15kcal mol−1), and a dispersion of 921±115K (1.83±0.23kcal mol−1). Finally, the effect of the electrostatic field of the 22 water molecules on the binding energies was investigated incrementally by symmetry adapted perturbation theory, in order to gauge the effect of the water environment on the binding energies. The results indicate that the extent of the electrostatic interaction of HF with ASW depends strongly on the properties of the binding site on the water cluster. We expect that this work will provide a solid foundation for a systematic development of a binding energy distribution database of small molecules on astrophysically relevant surfaces.