Geometric deep learning has recently achieved great success in non-Euclidean domains, and learning on 3D structures of large biomolecules is emerging as a distinct research area. However, its efficacy is largely constrained due to the limited quantity of structural data. Meanwhile, protein language models trained on substantial 1D sequences have shown burgeoning capabilities with scale in a broad range of applications. Several previous studies consider combining these different protein modalities to promote the representation power of geometric neural networks, but fail to present a comprehensive understanding of their benefits. In this work, we integrate the knowledge learned by well-trained protein language models into several state-of-the-art geometric networks and evaluate a variety of protein representation learning benchmarks, including protein-protein interface prediction, model quality assessment, protein-protein rigid-body docking, and binding affinity prediction. Our findings show an overall improvement of 20% over baselines. Strong evidence indicates that the incorporation of protein language models' knowledge enhances geometric networks' capacity by a significant margin and can be generalized to complex tasks.
How and where proteins interface with one another can ultimately impact the proteins' functions along with a range of other biological processes. As such, precise computational methods for protein interface prediction (PIP) come highly sought after as they could yield significant advances in drug discovery and design as well as protein function analysis. However, the traditional benchmark dataset for this task, Docking Benchmark 5 (DB5), contains only a modest 230 complexes for training, validating, and testing different machine learning algorithms. In this work, we expand on a dataset recently introduced for this task, the Database of Interacting Protein Structures (DIPS), to present DIPS-Plus, an enhanced, feature-rich dataset of 42,112 complexes for geometric deep learning of protein interfaces. The previous version of DIPS contains only the Cartesian coordinates and types of the atoms comprising a given protein complex, whereas DIPS-Plus now includes a plethora of new residue-level features including protrusion indices, half-sphere amino acid compositions, and new profile hidden Markov model (HMM)-based sequence features for each amino acid, giving researchers a large, well-curated feature bank for training protein interface prediction methods. We demonstrate through rigorous benchmarks that training an existing state-of-the-art (SOTA) model for PIP on DIPS-Plus yields SOTA results, surpassing the performance of all other models trained on residue-level and atom-level encodings of protein complexes to date.
Despite an explosion in the number of experimentally determined, atomically detailed structures of biomolecules, many critical tasks in structural biology remain data-limited. Whether performance in such tasks can be improved by using large repositories of tangentially related structural data remains an open question. To address this question, we focused on a central problem in biology: predicting how proteins interact with one another---that is, which surfaces of one protein bind to those of another protein. We built a training dataset, the Database of Interacting Protein Structures (DIPS), that contains biases but is two orders of magnitude larger than those used previously. We found that these biases significantly degrade the performance of existing methods on gold-standard data. Hypothesizing that assumptions baked into the hand-crafted features on which these methods depend were the source of the problem, we developed the first end-to-end learning model for protein interface prediction, the Siamese Atomic Surfacelet Network (SASNet). Using only spatial coordinates and identities of atoms, SASNet outperforms state-of-the-art methods trained on gold-standard structural data, even when trained on only 3% of our new dataset. Code and data available at https://github.com/drorlab/DIPS.