The authors propose the first end-to-end learning model for protein interface prediction, the Siamese Atomic Surfacelet Network (SASNet). The novelty of the method is that it only uses spatial coordinates and identities of atoms as inputs, instead of relying on hand-crafted features. The authors also introduce the Dataset of Interacting Protein Structures (DIPS) which increases the amount of binary protein interactions by two orders of magnitude over previously used datasets (DB5). The results outperform state-of-the-art methods when trained on the much larger DIPS dataset and are still comparable when trained on the DB5 dataset, showing robustness when trained on bound or unbound proteins. The paper is very well written and easy to follow. The problem is well characterised and the contributions and differences with state-of-the-art methods are very clear. Originality: This work is a novel combination of well-known techniques. It combines Siamese networks with 3D convolutional neural networks and minimises the binary cross entropy loss, as opposed to minimising the Euclidean distance as in classical Siamese approaches. This work is clearly separated from previous works and the contribution is well explained. Quality: The claims in the paper are well supported by experimental analysis. There is no mathematical notation or definitions in the paper, however the architecture of the model is well described. The authors also mention that their method lacks scalability as they can only train on 3% of the data but show how the performance would keep increasing as the data size increases. Clarity: The paper is very well written and organised. It is very easy to follow and gives detailed information about the model. The problem is very clear and the contribution well defined. Significance: This work does not require hand-crafted features since it is an end-to-end framework. The method modestly outperforms competitors, but the authors show that there is a lot of room for improvement that could originate from the sheer amount of data. Other comments: • For figure 2-E the 3D representation of the surfacelet is a bit confusing, since it seems like it is just a projection of the surfacelet in 2D, but that is not the case from what I understood when reading. No depth is depicted in the second cube in the figure. A more appropriate 3D figure could improve the understanding of the representation. • I believe that the second column in Table 3 should be DB5 trained instead of DB4 trained. Numbers are the same as Table 2 where performance was calculated from training on DB5. It could be possible that the reported number is the performance on the validation set from DB4. • In section 5.1 authors define CAUROC as the median per-Complex AUROC. Is this only used for the test set? In the caption of Table 2 the mean and standard deviation is reported across training seeds, but CAUROC is the column name. • The same problem happens for Figure 3 where the label for the y-axis is CAUROC but what we see there is the Mean AUROC and standard deviation. • For figure 3 it would be nice to see the CAUROC for the test set, so that the plot reaches 0.9 as reported in the results. Also, for the grid edge size, it seems like 27 should provide a more robust choice given the very small deviation. • 194: “we use a siamese-like networks where we…” should read: we use Siamese-like networks, or we use a Siamese-like network.

1. The primary message of the manuscript - that using a much larger dataset whose properties are somewhat different than those of the testing data provides improved performance of deep 3d convolutional networks - is more interesting to researchers in the application field than to ML researchers. 2. The use of 3d convolution for protein 3d structures is not new (e.g. ref [17]) as is the overall architecture for partner specific prediction (ref [23]). 3. The fact that the model is successful despite being presented with examples that do not reflect the unbound structures, by itself does not suggest by itself that the model has learned something about protein flexibility. In related work on interface prediction using ML, other authors have observed that performance remains quite good even for "hard" examples that exhibit conformational change upon binding. This kind of statement requires some kind of justification. Minor comments: 1. The references are numbered in the Reference list but are cited by author in the manuscript itself. 2. ref [17] is published in Bioinformatics. 3. "Xue et al. (2015) demonstrated that partner-specific interface predictors yield much higher performance." That is a review paper, so they did not demonstrate that. Better to cite ref [32] for that. 4. "Due to the homogenous, local, and hierarchical structure of proteins, we selected a three-dimensional convolutional neural network as SASNet’s underlying model" From this description it sounds like you should have chosen graph convolution, which is also rotation/translation invariant. 5. "In Figure 3B, we see that the dataset size tests yield consistently increasing performance, reflecting the high degree of scalability of our model, and implying that further performance gains could be obtained with larger dataset sizes." Figure 3B does not imply what is being said here. Although it does not seem like performance has saturated, that is a possibility. Furthermore, increasing performance does not reflect scalability.

Comments: - (lines 156-158) I understand the reasoning behind removing proteins with 30% sequence identity. Would it suffice to just remove those proteins which have similarity with the DB5 test set only, and keep the ones which are similar to the DB5 training set? This way, you get a larger training dataset without having the cross-contamination issue. - Instead of the proposed voxelizing technique (which can result in abrupt jumps if the atom falls closer to the voxel boundaries), would it help to use approaches which are smoother? For example, each atom could be modeled as a sphere of a certain radius, and each voxel would get a weight based on the area overlap with the sphere. - It is clear that the competing methods' hand-crafted features are unable to use the larger dataset to improve their performance. My guess is that some features are generalizable and some are not. A more careful study of this would be very informative. - It would be nice to have some information about the voxel size, number of voxels, how many amino acids does the input typically cover, etc in the experiments section. - Would the model be able to predict contact maps, or two regions within the same protein which interact with each other? If yes, then it opens up a few more options, like getting an even bigger training dataset, pre-training the models using contact map predictors, etc. - The experimental setup of Fig 3A could be better explained. Grid size here refers to the entire window surrounding the amino acid right? Is the voxel size kept constant or scaled appropriately? What happens if it is kept constant or scaled? Originality: Novel Clarity: The presentation of the paper is clear. Significance: Moderate