Thermodynamic Stability of Human γD-Crystallin Mutants Using Alchemical Free-Energy Calculations.

γD-Crystallin (HγDC) is a key structural protein in the human lens, whose aggregation has been associated with the development of cataracts. Single-point mutations and post-translational modifications destabilize HγDC interactions, forming partially folded intermediates, where hydrophobic residues are exposed and thus triggering its aggregation. In this work, we used alchemical free-energy calculations to predict changes in thermodynamic stability (ΔΔG) of 10 alanine-scanning variants and 12 HγDC mutations associated with the development of congenital cataract. Our results show that W42R is the most destabilizing mutation in HγDC. This has been corroborated through experimental determination of ΔΔG employing differential scanning calorimetry. Calculations of hydration free energies from the HγDC WT and the W42R mutant suggested that the mutant has a higher aggregation propensity. Our combined theoretical and experimental results contribute to understand HγDC destabilization and aggregation mechanisms in age-onset cataracts.

Parameterization of prototype organic small molecules suitable for OPVs and molecular dynamics simulations: the BTT and BPT cases.

Organic photovoltaics (OPV) have been theoretically studied within the usual parameters: open circuit voltage (Voc), short circuit current (Jsc), and fill factor (FF). The first two refer mostly to electronic properties, whereas the last contains all other possible contributions to cell efficiency, importantly including molecular geometrical and topological structures, both within a single molecule as amongst a system of molecules. In order to study the effects of molecular morphology of the heterostructures used in OPVs, molecular dynamic simulations (MDS) are imperative, and therefore parameterization of force fields to account for the description of planarity between aromatic rings, both intra- and inter-molecules, is of key importance. In this work, we present quantum mechanical analysis of geometry for the ground, and singlet and triplet excited states, of two simple prototypical molecules used to parametrize the corresponding force-fields. Central for this parameterization is the assignment of local charges within molecules; we studied and compared six different methods to assign atomic charges. With the parameters obtained, we performed molecular dynamics simulations of nanosystems of these molecules. Planarity effects and comparison between different methods for deriving atomic charges are investigated. These results can be applied in future MDS to interpret and characterize charge-transfer models in molecules suitable for OPV design. Graphical Abstract Depiction of a replicated system of BTT and BPT molecules after simulation.