Self-Consistent Convolutional Density Functional Approximations: Application to Adsorption at Metal Surfaces.

The exchange-correlation (XC) functional in density functional theory is used to approximate multi-electron interactions. A plethora of different functionals are available, but nearly all are based on the hierarchy of inputs commonly referred to as "Jacob's ladder." This paper introduces an approach to construct XC functionals with inputs from convolutions of arbitrary kernels with the electron density, providing a route to move beyond Jacob's ladder. We derive the variational derivative of these functionals, showing consistency with the generalized gradient approximation (GGA), and provide equations for variational derivatives based on multipole features from convolutional kernels. A proof-of-concept functional, PBEq, which generalizes the PBE α ${\alpha }$ framework with α ${\alpha }$ being a spatially-resolved function of the monopole of the electron density, is presented and implemented. It allows a single functional to use different GGAs at different spatial points in a system, while obeying PBE constraints. Analysis of the results underlines the importance of error cancellation and the XC potential in data-driven functional design. After testing on small molecules, bulk metals, and surface catalysts, the results indicate that this approach is a promising route to simultaneously optimize multiple properties of interest.

Unexplored Excipients in Biotherapeutic Formulations: Natural Osmolytes as Potential Stabilizers Against Thermally Induced Aggregation of IgG1 Biotherapeutics.

Monoclonal antibodies (mAbs), while incredibly successful, are prone to a variety of degradation pathways, the most significant of which is aggregation. One of the most commonly used strategy to overcome protein aggregation is addition of excipients to the formulation. Osmolytes such as trehalose, sucrose, and glycine are widely used. In this paper, we explore potential use of naturally occurring osmolytes such as betaine, sarcosine, ectoine, and hydroxyectoine for reducing aggregation of mAb therapeutics. Experimentation has been performed on two IgG1 mAbs via accelerated stability studies. A variety of analytical tools have been used for monitoring the impact, dynamic light scattering (DLS) for colloidal stability, Fourier transform infrared (FTIR) spectroscopy and fluorescence spectroscopy for conformational stability and the higher order structure (HOS), and differential scanning calorimetry (DSC) for thermal stability. No significant impact of osmolyte addition was observed on protein structure, on comparative Fc receptor (FcRn) binding, and on biocompatibility as per our hemolytic assay. Our results rank the osmolytes' stabilizing trend to be sarcosine > betaine > hydroxyectoine > ectoine. Sarcosine emerged as the most successful osmolyte rendering highest degree of protection against aggregation. Our data support the prospect of using these osmolytes as successful excipients for mAb formulations.