Predicting protein variant properties with electrostatic representations

Abstract

Does evolution capture the full functional potential of proteins, or is this potential restricted by selective pressures? If the former is true, providing variant effect prediction (VEP) models with evolutionary derived representations should be sufficient to guide the optimization of proteins. In the latter scenario, however, VEP models require different sources of information. In this work, we explore whether physics-based representations of protein variants benefit the performance of VEP models. More specifically, we explore electrostatic representations obtained from solving the Poisson-Boltzmann equation as novel features to fit VEP models to deep mutational scanning (DMS) data. We contrast and combine these representations with those derived from evolutionary models. To this end, we perform a range of experiments: benchmarking, ensembling with evolutionary models, accounting for assay conditions, and extrapolating to new screening data. Though our model displays significant predictive capacity, we find no instance where it provides a better alternative over existing evolutionary models, suggesting that electrostatic representations derived by our methods do not capture extra information compared to evolutionary representations.