Incorporating physics to overcome data scarcity in predictive modeling of protein function: a case study of BK channels.

Deep machine learning has brought many exciting breakthroughs in chemistry, physics and biology. These models require large amount of training data and struggle when the data is scarce. The latter is true for predictive modeling of the function of complex proteins such as ion channels, where only hundreds of mutational data may be available. Using the big potassium (BK) channel as a biologically important model system, we demonstrate that a reliable predictive model of its voltage gating property could be derived from only 473 mutational data by incorporating physics-derived features, which include dynamic properties from molecular dynamics simulations and energetic quantities from Rosetta mutation calculations. We show that the final random forest model captures key trends and hotspots in mutational effects of BK voltage gating, such as the important role of pore hydrophobicity. A particularly curious prediction is that mutations of two adjacent residues on the S5 helix would always have opposite effects on the gating voltage, which was confirmed by experimental characterization of four novel mutations. The current work demonstrates the importance and effectiveness of incorporating physics in predictive modeling of protein function with scarce data.