Improving the prediction of protein stability changes upon mutations by geometric learning and a pre-training strategy.

Accurate prediction of protein mutation effects is of great importance in protein engineering and design. Here we propose GeoStab-suite, a suite of three geometric learning-based models-GeoFitness, GeoDDG and GeoDTm-for the prediction of fitness score, ΔΔG and ΔT of a protein upon mutations, respectively. GeoFitness engages a specialized loss function to allow supervised training of a unified model using the large amount of multi-labeled fitness data in the deep mutational scanning database. To further improve the downstream tasks of ΔΔG and ΔT prediction, the encoder of GeoFitness is reutilized as a pre-trained module in GeoDDG and GeoDTm to overcome the challenge of lacking sufficient labeled data. This pre-training strategy, in combination with data expansion, markedly improves model performance and generalizability. In the benchmark test, GeoDDG and GeoDTm outperform the other state-of-the-art methods by at least 30% and 70%, respectively, in terms of the Spearman correlation coefficient.