DeepPCM: Predicting Protein-Ligand Binding using Unsupervised Learned Representations
Authors: Paul Kim
Robin Winter
Djork-Arné Clevert
Venue:  (2020)
Keywords: Unsupervised Representation Learning
Computational biology
computational chemistry
protein-ligand binding

Abstract: In-silico protein-ligand binding prediction is an ongoing area of research in computational chemistry and machine learning based drug discovery, as an accurate predictive model could greatly reduce the time and resources necessary for the detection and prioritization of possible drug candidates. Proteochemometric modeling (PCM) attempts to make an accurate model of the protein-ligand interaction space by combining explicit protein and ligand descriptors. This requires the creation of information-rich, uniform and computer interpretable representations of proteins and ligands. Previous work in PCM modeling relies on pre-defined, handcrafted feature extraction methods, and many methods use protein descriptors that require alignment or are otherwise specific to a particular group of related proteins. However, recent advances in representation learning have shown that unsupervised machine learning can be used to generate embeddings which outperform complex, human-engineered representations. We apply this reasoning to propose a novel proteochemometric modeling methodology which, for the first time, uses embeddings generated via unsupervised representation learning for both the protein and ligand descriptors. We evaluate performance on various splits of a benchmark dataset, including a challenging split that tests the model’s ability to generalize to proteins for which bioactivity data is greatly limited, and we find that our method consistently outperforms state-of-the-art methods.

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DEEPPCM: PREDICTING PROTEIN-LIGAND BINDING USING UNSUPERVISED LEARNED REPRESENTATIONS
Anonymous authors
Paper under double-blind review
ABSTRACT
In-silico protein-ligand binding prediction is an ongoing area of research in com- putational chemistry and machine learning based drug discovery, as an accurate predictive model could greatly reduce the time and resources necessary for the detection and prioritization of possible drug candidates. Protenchemometric mod- eling (PCM) attempts to make an accurate model of the protein-ligand interac- tion space by combining explicit protein and ligand descriptors. This requires the creation of information-rich, uniform and computer interpretable representations of proteins and ligands. Previous work in PCM modeling relies on pre-defined, handcrafted feature extraction methods, and many methods use protein descrip- tors that require alignment or are otherwise specific to a particular group of re- lated proteins. However, recent advances in representation learning have shown that unsupervised machine learning can be used to generate embeddings which outperform complex, human uuman-engieeered representations. We apply this reason- ing to propose novel proteochemometric modeling methodology which, for the first time, uses embeddings generated via unsupervised representation learning for both the protein and ligand descriptors. We evaluate performance various splits a benchmark dataset, including a challenging split that tests the model's ability to generalize to proteins for which bioactivity data is greatly limited, and we find that our method consistently outperforms state-of
ootte--f--hharrr thehhrrrt methods.
INTRODUCTION
main goal of cheminformaties in the area of drug discovery to model the interaction of small molecules with proteins in-silico. The ability to accurately predict the binding affinity of ligand towards a biological target without the need to conduct expensive in-vitro experiments has the po- tential to accelerate the drug development process by enabling early prioritization of promising drug candidates (Cortés-Cinine Ciriano et al. 2015). A common approach to train a machine learning algo- rithm predict the binding affinity of ligands towards certain biological target using training set of compounds that have been experimentally measured on this target. This modality is commonly referred as quantitative arrucurreaacivvityyellaiinnsss (QSAR) model (van Westen al. 2011).
QSAR models can be broadly classified into two types: single-task QSAR models and multi-task QSAR models (Figure[]. single-task QSAR modeling, model is trained separately for each pro- tein to predict a binary or continuous outcome (binding vs not-binding or the binding affinity) given compound input. The machine learning model used could be anything from logistic regression to deep neural networks (Lenselink et al. 2017] Cherkasov et al., 2014 In multi-task modeling, single model is trained to predict binding across multiple proteins simultaneously. allowing the model to take advantage of the correlations in binding activity between compounds on different tar- gets (Caruana 1997 Yuan et al., (016). This is done, for example, by using a neural network with multiple output nodes where each output node corresponds to different protein. Thus, multiple outputs are predicted given a compound input (Simöes et al. 2018 Dahl et al. 2014).
While these methods have been employed on various protein targets, there are methodological con- cerns to their use (Lima et al.) 2016; Mitchell 2014). Both single-task and multi-task models must be retrained from scratch if one wishes to incorporate binding data for new protein, and both cannot be used at all to make predictions on new protein targets for which experimental data is absent (van Westen et al. 2011).

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An attractive solution to this problem is to also include protein information in called pro- teochemometric model (Figure D. The additional protein information enables a PCM model to directly utilize similarities between proteins for bioactivity modeling (Cortés- Cirian- et al. 2015 van Westen et al. 201T). This leads to many potential benefits over classical QSAR single-task and multi-task modeling. First, proteins are explicitly represented by defined featurization, PCM models can be used to make activity predictions on proteins without pre-existing bioactivity data, which is impossible with single-task or multi-task modeling. They can also be used to model binding on proteins for which experimental data may be too limited to train an effective single-task model (van Westen et al. 201 Second, with an expressive protein descriptor, model could leverage similarities and differences between proteins directly to model their binding behaviors, rather than merely using correlations found among the compounds they bind to, as multi-task modeling, or ignoring protein relationships altogether as in single-task modeling (Cortés-Ciriano et al. [2015] van Westen et al., 2211T) Consequently, PCM models have found success on a variety of protein targets,
and using many different machine learning methods, including random forests and SVMs (Ballester
& Mitchell 2010 Weill et al.] 2011 van Westen et al. 2013) Shiraishi et al.
2013
Cheng et al.
2012).
Single-Task
Multi-Task
PCM
Compound Descriptor
Compound Descriptor
Compound Descriptor
Compound Descriptor
Target Descriptor
Model for All Targets
Model for Target A
Model for Target B
Model for All Targets
Prediction for
Prediction for Target B
Prediction
Prediction
Target A
Prediction for Described Target
Figure 1: Depiction of the architectures of different ligand-targen binding-affinit prediction models.
Recent advances in the field of Deep Learning have also led to its use in QSAR single and multi- task modeling as well as PCM modeling (Lenselink et al.] 2017; Menden et al., 2013 LeCun et al. 2015 Schmidhuber 2015). Lenselink et al.] (2017) compared deep learning methods against other machine learning methods for PCM, single-task QSAR, and multi-task QSAR models on a bench- mark dataset, and the authors found that PCM models using deep neural networks outperform other machine learning methods as well as single-task and multi-task QSAR models.
All of the aforementioned works make features for both the small molecules and the proteins based on hand-crafter feature extraction protocols. Small molecules are often represented by counting and aggregating smaller substructures, while proteins are often represented by aggregation of computed physio-chemical features of their amino-acids or by encoding the differences in aligned sequences.
In many application domains of Deep Learning, recent research has shown that these methods gen- erally work better when the input data representation is lower-level and unabstracted, allowing the model learn hierarchical features directly rather than relying on features which are hand-crafted by humans (LeCun et al. 2015) Schmidhuber, 2015). For example, this is the case in computer vision, where deep learning on pixel value features has been the state of the art for several years (Schmid- huber 2015). In cases where the input space is too high-dimensional, and especially if there is not enough labeled data to train a model end-to-end, unsupervised representation learning is used to generate wiwer-dimensionll embeddings, again relying machine learning, rather than human en- gineering, for feature extraction. This is the case in natural language processing, as well as in video analysis (Srivastava et al. 2013 Erhan et al. 2010 Mikolov et al. 2013).
In this work, we follow this reasoning and utilize such unsupervised-leanme learned embeddings to repre- sent both the ligand and protein spaces for proteochemometric modelling. To the best of our knowl-
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edge, we combine, for the first time, compound and protein representations both generated by deep learning models that were pretrained on an unsupervised learning task, as inputs to a PCM model. Moreover, believe that this is the first work which combines unsupervised-leamee of biological and chemical entities simultaneously in order to solve a downstream task.
embeddings
1.1 COMPOUND DESCRIPTORS
The following section describes the currently used handcrafted ligand descriptors, evaluates their properties, and introduces the ligand descriptors that we use for our model known as CDDD descriptors - which are generated via unsupervised machine learning.
Handcrafted Compound Deseriptors The state-of-the-art compound descriptors that are used for a vast majority of PCM and other chemoinformatics tasks are different varieties of circular fin- gerprints. In binary keyed circular fingerprints, each bit refers to specific substructure's presence or absence in the molecule, while in counts format the bits refer to the number of occurrences of the substructure (van Westen et al., 2011 Glen al., 2006 Rogers & Hahn 2010). As the number of potential substructures is vast (~222), the resulting sparse set of bits is usually hashed and folded to a much smaller size (~10") at the expense of hash and bit collisions (Rogers & Hahn 2010). These structure-based descriptors can be augmented with physicochemical descriptors, such DRAGON or PaDEL., along with other chemical descriptors like atom identity/type, MACCs keys, and topo- Yap 2011).
logical indices (Mauri et al. 2006
Issues Circular fingerprints contain information about only the presence or absence of certain sub- structures in the compound they thus fail to capture the shape or arrangement of those substructures within the compound. Furthermore, fingerprints rely on a hashing protocol to compress the millions of different substructures that are recorded into smaller vector
result, hash collisions can mean that completely different substructures can correspond to the same fingerprint bit. This also means that one cannot determine which exact substructures are responsible for the model prediction.
CDDD - Ligand Descriptor To avoid these issues, we use the CDDD (Continuous and Data Driven Molecular Descriptors), a model for the generation of diwer-dimensional representation vec- tors of molecules developed by Winter et al. (2019). This model uses recurrent autoencoder trained on the task of translating non-canonical SMILES string representations of compounds into their canonical form. After unsupervised learning on approximately 72 million compound SMILES, given compound is represented by the 512-length bottleneck of the translation model, and thus is encoded into a 512-length vector. These embeddings have been shown to be effective on QSAR prediction and virtual screening tasks (Winter et al., 2019).
CDDD descriptors offer unique, compact, and continuous vector representation for each com- pound, as opposed to fingerprints, which are non-unique, discrete, and must be hashed to be made compact. Molecules with the same substructures but differently arranged will correspond to dif- ferent vectors. Additionally, these mnsupervised-leamee descriptors have demonstrated competitive superior results compared to molecular fingerprints variety of other tasks, indicating their ability to effectively represent compound properties and behaviors (Winter et al. 2019). A diagram can be found in Appendix section D
1.2 PROTEIN DESCRIPTORS
Next, we describe the various methodologies used for handcrafted protein descriptors. There are many different examples of highly specialized protein Ceature-extractio protocols used for PCM models that operate over narrow range of targets. We describe the broad categories, examine their drawbacks and introduce the unsupervised protein descriptor which we use, known UniRep.
Handerafted Protein Descriptors Most commonly used protein descriptors can be described as either amino-acid-basee based, or sequence-based. Amino-acid-bar based descriptors are computed us- ing some combination of physicochemical and structural properties of individual amino acids. For example, the commonly used Z-scale descriptors and their counterpart ProtFP descriptors are con- structed by computing various amino acid physicochemical properties (such as hydrophobicity or polarity), taking PCA over these properties, and then representing each amino acid by its first few principal components (Sandberg et al. 1998 van Westen et al. 2013). These descriptors can be combined with structural information descriptors, such normalized van der Waals volume, charge,
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and the secondary structure of the protein at that amino acid residue (Lapins et al. 2013). The whole protein is then represented by aggregating the amino-acid descriptors over the whole sequence.
Sequence-based descriptors constructed by taking aligned sequences regions and using en- codings to represent the amino acid identity at a given location in the aligned region. For example, in Nabu al. (2015), the authors build model that predicts the bioactivity type penicillin binding proteins based on the positions the mutations in the sequence. This was done by aligning the protein sequences and uniquely representing the positions mutation may have occurred at with a one-hot-encoding. Thus, from 75 potential mutation sites, a 75-length vector is returned for each protein. Other variations of this technique use motifs or encodings of multiple varying segments (Lapinsh et al. 2005).
mutated vs wild
Additionally, on proteins for which 3D-information is available, this information can be incorporated into the protein descriptor. Methods vary in general, 3D-models, for example crystal structures or water-field maps, are first aligned. Subsequently, descriptors are built based on amino acid identity at specific positions at the binding pocket or taking a PCA over the aligned field maps (van Westen
ct al. 2013 Lapinsh et al. 2005 Subramanian et al. 2016 Kruger & Overington 2012).
Amino acid-based descriptors require crude aggregation or binning methods, they must convert variable length sequences of amino acids into a constant- -leggh vector. For example, a com- mon strategy is to divide the sequence into equal-length segments, then average over the descriptors for each segment (Lenselink et al. 2017; van Westen et al., 2013). This leads to the undesirable property where a single amino acid insertion early in the sequence would shift all subsequent seg- ments, thus changing every descriptor bit despite a small change to the protein itself. Additionally, motifs and functional domains have variable numbers of amino acids which are not necessarily con- tiguous, so averaging over fixed-length contiguous segments can fail to capture relevant features consistently.
Issues
Sequence and 3D-structure based descriptors must be aligned, which restricts the usable bioactivity data to only very small fraction of closely related proteins for which an alignment is meaningful. These descriptors also cannot be applied to new regions of the protein space, where bioactivity measurements of similar proteins are unavailable. Essentially, these methods build descriptors that are explicitly based on the differences between a few proteins, which greatly limits the scope of the problems that can be approached with such descriptors, as well as the amount of data that can be leveraged to train models. These data availability issues are exacerbated when using 3D 3D-dessripsors, since 3D structures are only available for a subset proteins.
UniRep Protein Descriptor We use UniRep developed by Alley et al. (2019), which uses multiplicative LSTM architecture on approximately 24 million protein amino acid sequences taken from UniRef50 (Krause et al. 2016). The UniRep model is trained on the next-character ceraraccte--redcction task, where the LSTM predicts the next amino acid in the protein sequence given the previous amino acids. To generate fixed-length embeddings, the hidden states of the model that are generated during the forward pass are averaged over the sequence dimension. For implementation details, refer to Alley al. 2019). The pre-trained model can be used out-of-the-boot taking as input amino acid sequences and outputting embeddings of length 64, 256, or 1900 depending on the architecture used. For the PCM model which we propose here, we found that the 256-1ength embeddings performed best, and so we will use UniRep to refer to the 256-1ength UniRep descriptor in this paper. A diagram can be found in Appendix section
UniRep descriptors offer many advantages over their handcrafted counterparts. The descriptors are alignment-fir free sequence-based representations, which therefore allow the utilization of protein bioactivity assay data across families and species instead of just highly similar proteins. greatly increasing the available training data. Moreover, these descriptors do not require 3D--stucctuee in- formation, which is available for only a small subset of proteins. Additionally, there is no need for binning or averaging across arbitrary length contiguous chunks of sequence.
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2 METHODS
2.1 DATASET AND EVALUATION
We evaluate on a large-scale benchmark PCM dataset created in Lenselink et al. (2017), which contains 310k compound-pree protttinnnppteiinnnomm bioactivity measurements taken from exclusively the highest- confidence bioactivity assay data ChEMBL. The dataset is comprised of 1226 unique human proteins from range of protein families, and 190k unique compounds.
For validation purposes, we use three different types of hold-out-sets: random and temporal splits, which are included in Lenselink al. (2017), and low-coverage-protee splits, which is new and more challenging criterion/splitting Random splits randomly divide the bioactivity measurements into train, valid, and test sets, with the validation set used for early stopping. A drawback of the random split is that it can assign bioactivity measurements from the same experimental assay into the training and test sets. Since single assay can involve similar, congeneric compounds, it is likely that there will be compounds in the training set that are highly similar to compounds in the test set and measured on the same protein. This split can thus report overly optimistic results (Lenselink) er al., (017). Therefore, experiments are performed this problem by splitting measurements from experimental batches done during or after 2013 into the test set, and using batches done pre-2013 for the training and validation set.
temporal split, which attempts to overcome
Ultimately, we would like to assess the ability of the model to generalize to protein targets that only have very few experimental measurements for training. This setting is more challenging but also more relevant for demonstrating a PCM model's potential, since PCM models should be able to utilize relationships in the protein descriptor space infer proteins that have not been well covered in the training set. We therefore apply a final, more challenging split the low-coverage split. Here, we create several data folds by randomly selecting small numbers of proteins and then randomly selecting 90% of the bioactivity measurements on these proteins to be held out as a test set. The remaining 10% of the measurements on these proteins are included in the training set, along with all the bioactivity measurements from the other proteins. Thus, the hold-out set of the low-coverage split only contains proteins for which there low data coverage in the training set.
All hyperparameter optimization of our model was performed on the temporal split, and the best performing hyperparameter scheme on the validation set the temporal split was used to train models on the random and cow-coverage-protee splits. Early stopping on the validation set was used for the random and temporal splits, while the low-coverage splits were trained for a fixed number of epochs. For the random and temporal splits, we use bootstrapping over 25 bootstrapped samples to estimate the standard error of the various models, and we compute Wilcoxon signed- rank-test p-values over the bootstrapped samples determine the significance of our results, while on the low-coverage split we compute Wilcoxon p-values over the paired held-out proteins (Demšar) 2006).
2.2 DESCRIPTORS
For our models, we use the unsupervised-leamed UniRep and CDDD descriptors as described above. The handcrafted benchmark model which we compare against uses 4096-bit circular fingerprint de- scriptors plus six computed molecular physicochemical properties for the ligand. For the protein, the handcrafted benchmark computes amino-acid across 20 equal-length parts of the protein sequence (Lenselink et al. 2017).
ciroo--ccrrpprrtt------ property-basee features and averages these properties
2.3 MODELS
DeepPCM The DeepPCM model is a feedforward neural network with fully connected layers. We first apply (0, 0.01) Gaussian noise to the compound inputs and (0, 0.05) Gaussian noise to the protein inputs for data augmentation and generalization purposes. The noised inputs are passed through separate bottleneck layers, each with 128 nodes. The bottleneck outputs and original noised inputs are concatenated together, to allow the rest of the model to use either the transformed features from the separate bottlenecks, inputs a trick used in many recent neural network architectures (Huang et al. 20177; He et al.) 2016). This concatenated vector is fed into two fully connected layers, with 2048 and 1024 nodes
learn features from the raw compound and protein
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Table I: Results for the random and temporal split experiments performed on the benchmark dataset.
Results for the Single- and Multi-Task QSAR model (*) were taken from Lenselink et al. (0177). Bold indicates results where our model exhibited highly statistically significant (p < 0.0005) im- provement over the Benchmark model. InteNoonnteraction--I1 scriptors; UD: Unsupervised-leame Descriptors; UP: Unsupervised Protein Descriptor; UC: Unsu- pervised Compound Descriptor; HP: Handcrafted Protein Descriptor; HC: Handcrafted Compound Descriptor
Baseline; HD:Handcrafted De-
Random
Temporal
Model
MCC
BEDROC
MCC
BEDROC
Single- Task QSAR
0.53
0.91
0.22:0008
0.73+0000
Multi-Task QSAR *
0.57
0.92::0.05
0.26+0.07
0.761:0.06
NIB + HD
0.529+00012
0.954=0.004
0.287=0.016
0.776++0001
NIB + UD
0.543
0.954=000003
0.30440.005
0.787++0.006
Benchmark
0.073
0.958
0.304
0.799-10.020
DeepPCM + UP HC
0.619:0.004
0.968=0.002
0.317+0.007
0.820=0.010
DeepPCM + HP UC
0.589-00.031 0.069
0.351+00013
0.828+
DeepPCM + UP + UC
0.600--0.008
0.903
0.353+00000
0.839
respectively. Dropout regularization is used throughout. Details about the model architecture and hyperparameters can found the Appendix sections A and
No-Interaction-Termm Baseline In addition, to evaluate the contribution from compound-protd interaction terms, we include a no-interaction-termy model that does not allow information flow between proteins and compounds. This model processes protein and compound inputs in separate networks, with the final predictions from each network averaged to then give a final output for the model. A diagram is included in the Appendix section B
Benchmark Model We compare against a PCM model developed in Lennesln et al. (0117), which uses three-layer fully-comnected pyramidal neural network. A diagram can be found in the Ap- pendix section [ The authors compare this model against single-task and multi-task QSAR models well other deep learning architectures their benchmark PCM dataset and find this model to perform best.
2.4 METRICS
The models and parameter settings are compared using Matthews Correlation Coefficient (MCC) and Selzzmann-Enhancee ROC (BEDROC) (Lenselink al. 2017). The MCC score represents the overall model quality and is especially useful for measuring performance on unbalanced datasets. The BEDROC score a metric that represents the effectiveness of the model for compound prioriti- zation since often, only a small subset of in-silico screened compounds can be tested experimentally, useful model will rank active compounds very highly (Truchon & Bayly] (2007). The BEDROC score represents this by weighting the ROC results such that 80% of the BEDROC score comes from top 8% of predicted actives. Thus, it is analogous to ROC-50 score.
RESULTS
Overall, all splits and metrics, we find that our method outperforms the benchmark model with high statistical significance (p < 0.0005). On the random split, we find a 10% improvement in MCC from using model compared to the benchmark, and 10% improvement in MCC compared to the best multi-task QSAR model run Lenselink et al. (2017) on this dataset. On the temporal split, the improvement is greater: 16% increase in MCC compared to the benchmark and 36% increase in MCC compared to the best multi-task model.
also find that our method significantly outperforms the benchmark. In Figure 2a, the per per-protein-targe MCC results of our model vs the benchmark model are plotted. Our model, based the unsupervised-leanen descriptors, shows average better performance.
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When applying a Wilcoxon signed-ranked test find this difference to be highly significant (p 4.1 4.1*10").
A: Chsupervised va Handcrafted
B: Unsupervisdd vs No-Isteraction Unsupervised C: Handerafaad vs No No-Interaction Handeraffod
6.
MCC Coviggeen Devrtteee
MCC Unassperrces Diseetpoies
MCC- Hunterrleed Draecruttttts
12
62
62
6.
2.0
64
-20 07
91 02 6. 05 05
0.5 -0.3
51
35
0.3
54 0N
00 03. -0361
02 05 0. Ba 26
Handenfted Desorppoes
Shsapervied Descriptoes
No-fiteractions Bandorafied Descrigtoes
Figure 2: Scatterplot of pairwise MCC performance per protein on the low-coverage split. Panel A compares the DeepPCM model with unsupervised-Jearnee descriptors to the benchmark model with handcrafted descriptors. Panels B and C compare the performance of the full models versus the No- Interaction- Terms models when using unsupervised-lent The blue line indicates the diagonal, where performance for both models would be equal.
or handcrafted descriptors respectively.
DISCUSSION
The results are consistent with our expectation that the descriptors generated via unsupervised repre- sentation learning would be significantly more powerful than the handcrafted protein and compound descriptors.
In order to elucidate the individual impact of each descriptor type we also train models using unsu- pervised descriptors for either the ligand or the protein, and handcrafted descriptors for the other. We find that replacing the handcrafted compound descriptor with the unsupervised compound descriptor responsible for the largest increase in performance on the temporal split, with the unsupervised protein descriptor providing very small improvement (see Table D.. We note that we did not tune the network architecture or hyperparameters for these descriptor combinations as a result, we might expect performance to be slightly different if the models were to be fully optimized. However, believe that these experiments broadly illustrate which descriptors are responsible for the perfor- mance improvement.
Furthermore, we compare performance of the DeepPCM model on all splits with performance on the Noo-Interaction-Tee model, using both handcrafted and unsupervised-leamed descriptors. By comparing these two models, we can investigate the difference between the full model, which is potentially able to model the specific bio-chemical interaction between the protein and the ligand, versus a model that can only recover compound and protein bias in the dataset.
We find that models with interaction terms between the protein and ligand perform significantly bet- ter than the ---Inerrattion-ermm model across all metrics and splits, which is consistent with our expectation that the model is able make predictions based on specific protein-ligand binding in- formation, and is not merely collapsing to predict the protein or compounds independent propensity for binding, which is what the So--Interaction-Tees Teriiioo---ee---eee porms-model is restricted to (T.ble
Just as when using full models with interaction terms, we find that the No-Interaction Terms model using nnsupervised-learnee descriptors performs better than the No- No-Interaction- Terms model us- ing handcrafted descriptors, which suggests that the unsupervised-leamed descriptors contain more useful information on which to learn general features of proteins and compounds that make them more or less likely to be binding overall. Additionally, we find that the improvement in perfor- mance from using the full models rather than the No-Interactionn-Teee Terims models is greater when using unsupervised-leameed descriptors than when using handcrafted descriptors. For example, the temporal split, the unsupervised-leann learned descriptors improve performance on the DeepPCM model by 16% relative the No-Interaction-TTen model with unsupervised-learmed descriptors,
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while the handcrafted deseriptors improve performance the benchmark model by only 6% rela- tive to the co-Interaccton-Tene Terms model with handcrafted descriptors (Table D. This suggests that the mnsupervised-leameen greater degree than do handcrafted descriptors.
descriptors facilitate the learning of actual protein protein-ligand interactions to
This finding is supported by the results the tn--protein-coverrge split, where Figures 2B and 2C depict the difference between the full models and the to-Interaatton-Termm models when using unsupervised-leanen
descriptors and handcrafted descriptors respectively. The DeepPCM model significantly outperforms the No-Interaction- Terms model when the unsupervised-lcangn descrip- tors are used as input (p = 2.1 1.1*10 (). This is not the case when handcrafted features are used, where the difference in performance between the benchmark model and the No-Interaction- Terms model not significant (p= = 0.10).
Taken together, these results indicate that the unsupervised-leamee descriptors - despite being more compact representations that were not specifically trained for the PCM task but instead learned in fully unsupervised manner are able to not only store more meaningful information about protein or ligand's overall binding propensity, but also that they are more useful for learning higher- order features required to model the specific binding interaction of given protein and ligand.
CONCLUSION
In this work proposed proteochemometric model that utilizes feature extraction method for both ligand and target that was pre-trained on an unsupervised learning task. We demonstrated how PCM model based on these descriptors significantly outperformed state-of-the-arr hand-crafted descriptors in various experiments, including the impactful low-protein-coverag split. Looking for- ward, believe that with sufficient data, PCM models could be powerful enough to replace much of the expensive and time-consuming in-vitro experimentation required to develop new drugs, and could also find applications in precision medicine for example to examine the influence of muta- tions in viral, cancerous, or otherwise modified proteins their binding activity. More broadly, we hope that by demonstrating the power of unsupervised pre-trained embeddings on a biological task, this work inspires further research improve currently existing machine learned representations of compounds and proteins, to generate new representations of biological and chemical entities such RNAs, antibodies and cell lines, and to apply these representations solve difficult problems in the life sciences.
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10

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Under review as a conference paper at ICLR 2020
A
DEEPPCM MODEL ARCHITECTURE
DeepPCM
Compound Descriptor
Protein Descriptor
Gaussian Noise (0, 0.01)
Gaussian Noise (0, 0.05)
Compound Bottleneck (128)
Protein Bottleneck (128)
Dropout (0.2)
Dropout (0.2)
Concatenate (128 + 128 + len(compound) + len(protein))
Dropout(0.25) (ReLU(fullyConneeted (2048)))
Dro5out(0.25) (Renu(fullyConnected (1024)))
FullyConnected (1)
Figure Architecture and Hyperparameters for the DeepPCM model.

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Under review as a conference paper at ICLR 2020
B NO-INTERACTION-TERM. BASELINE ARCHITECTURE
No Interaction Terms Baseline
Compound Descriplor
Protein Descriplor
Gaussian Noise (0, 0.01)
Gaussian Noise (0, 0.05)
Compound Bottleneck (128)
Protcin Bottleneck (128)
Dropout (0.2)
Dropout (0.2)
Concatenate (128 len(compound))
Concatenate (128 len(protein)
Dropou((0.25) (Reiifflleed (1024)))
(002 (ReL.UfFullyCommete (1024)))
(ropout(0.25)) (ReLLU(fullyCommecled (512)))
Dropout (ReLU(Fullyyoommeee (512))
FullyConnected (1)
FullyConnected (1)
Average
Figure 4: Architecture and Hyperparameters for the No-Interaction-Tere Terms Baseline model.
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Under review as a conference paper at ICLR 2020
C
BENCHMARK MODEL ARCHITECTURE
Benchmark Model
Compound Descriptor
Protein Descriptor
Concatenate (len(compound) + len(protein))
Dropout(0.25) (ReL (4000)))
Dropout(.225)RRe)) (ReL.U(FullyComecceed (2000))))))))))))))
Dr05)ut(0.25) (ReLuuFullyConmeeted ( (1000)))
FullyConnected (I)
Figure 5: Architecture and Hyperparameters for the benchmark model from Lenselink al. (201))
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Under review as a conference paper at ICLR 2020
D CDDD DIAGRAM
Representation
Translation
Representation 2
1,3-Benzodioxole
Encoder
Decoder
c1ccc2c(c1)oco2
Molecular Descriptor
Figure 6: General architecture of the translation model, using the example of translating between IUPAC and SMILES representations of 1,3-benzodioxole. The final CDDD model translates from non-canonical to canonical SMILES representations of compounds. Figure and text taken from Winter et al. (2019) with permission from the authors.
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Under review as a conference paper at ICLR 2020
E
UNIREP DIAGRAM
Train
GFP: NEKGREL... UniRef50
Target
S
entrapy
K
eetropy
Prediction
Aoieltd Whanat
A Flatu &
Softnox Fongaaccion
Soltroo Hngrwosen
mLSTM
mLSTM
M
Numefioa Sunmary up ISM
Name Sumtarry 4p
UniRep
Apply
Diverse tasks
fundamental Teatures
Sementic Similertyy
Top Model
Distance
Single Reiuon
Secondary
Stabiity
Figure 7: Workflow learn and upply deep protein representations. a. UniRep model was trained on 24 million UniRef50 primary amino acid sequences. The model was trained to perform next amino acid prediction (minimizing cross-entropy loss), and in so doing, was forced to learn how to internally represent proteins. b. During application, the trained model is used to generate a single fixed-length vector representation the input sequence by globally averaging intermediate mLSTM numerical summaries (the hidden states). A top model (e.g. sparse linear regression random forest) trained on top of the representation, which acts as a featurization of the input sequence, enables supervised learning diverse protein informatics tasks. Figure and text taken from Alley et al. (2019) with permission from the authors.
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Under review as a conference paper at ICLR 2020
F HYPERPARAMETERS
The table indicates the hyperparameters that were tested for the DeepPCM model. Bold indicates the hyperparameters that were chosen for the final model based on performance the validation set of the temporal splits.
Table 2:
Hyperparameter
Values
Learning Rate
0.05, 0.01, 0.005, 0.001, 0.0001
Optimizer
SGD, NAG SGD w/ Momentum, ADAM
Early Stopping Patience
5, 20, 50, 100
Compound Input Noise SD
0, 0.01, 0.05
Protein Input Noise SD
0, 0.01, 0.05, 0.1
Architectures
Wide( > 1000 neurons/layer), Deep ( (>4 layers)
Architecture cont'd
Wide + Deep, Shallow( <3 layers). Shallow Wide
Weight Decay
0.0001, 0.00001
Learning Rate Decay
Constant, On Plateau
Dropout
All 0.5, All 0.25, All 0.1, 0.5 in early layers and decaying to 0.1
Activation Functions
ReLU, TanH, Sigmoid, LeakyReLU, Swish
16


Reviews:
[{"review_id": "HJxiMPIitS", "reviewer": "AnonReviewer1", "summary": "", "questions": "", "limitations": "", "rating": 1, "confidence": null, "soundness": null, "presentation": null, "contribution": null, "strengths": "", "weaknesses": "", "quality": null, "clarity": null, "significance": null, "originality": null, "strengths_and_weaknesses": "", "was_revised": false, "final_justification": "", "rebuttal": "", "claims_and_evidence": "", "methods_and_evaluation_criteria": "", "theoretical_claims": "", "experimental_designs_or_analyses": "", "relation_to_broader_scientific_literature": "", "essential_references_not_discussed": "", "other_strengths_and_weaknesses": "", "other_comments_or_suggestions": "", "questions_for_authors": "", "summary_of_paper": "", "summary_of_recommendation": "", "technical_quality": "", "clarity_of_presentation": "", "potential_impact": "", "robotics_focus": "", "quality_of_limitations": "", "questions_for_rebuttal": "", "reasons_to_accept": "", "reasons_to_reject": "", "questions_to_authors": "", "main_review": "", "summary_of_the_paper": "", "summary_of_the_review": "", "strength_and_weaknesses": "", "limitations_and_societal_impact": "", "review_text": "This paper proposes to learn representations of protein and molecules for the prediction of protein-ligand binding prediction.\n\nThe presentation of this paper is a bit lengthy and repetitive in some cases. The long descriptions of protein/drug descriptors are a nice overview,  but it may be unnecessary as the authors in the end use other works’ embedding.\n\nThe author points out that there are interpretability issues & the inability to capture the shape of the substructures with previous ligand descriptors, however, it seems that CDDD also is not interpretable and could not capture the shape as it operates on SMILES strings, although seems to have better predictive performance.\n\nFor the protein descriptor, the author is missing several important descriptors that may not have the issues mentioned such as Protein Sequence Composition descriptor. \n\nThe technical novelty is very limited. It seems the usage of CDDD and UniRep are its only difference from previous works such as DeepDTA, WideDTA, DeepConv-DTI, PADME and CDDD and UniRep are also from other works. It may be more suitable for a domain journal instead of ICLR which focuses on method innovation. \n\n\nThe experimental setup is solid with realistic considerations. However, it is missing many baselines such as DeepDTA, WideDTA, DeepConv-DTI, PADME and more classic methods such as SimBoost and KronRLS. ", "extra_scores": {"experience_assessment": "I have published in this field for several years.", "review_assessment:_checking_correctness_of_derivations_and_theory": "I did not assess the derivations or theory.", "review_assessment:_checking_correctness_of_experiments": "I carefully checked the experiments.", "review_assessment:_thoroughness_in_paper_reading": "I read the paper thoroughly."}, "extra_text": {}}, {"review_id": "H1lbzsATKB", "reviewer": "AnonReviewer2", "summary": "", "questions": "", "limitations": "", "rating": 3, "confidence": null, "soundness": null, "presentation": null, "contribution": null, "strengths": "", "weaknesses": "", "quality": null, "clarity": null, "significance": null, "originality": null, "strengths_and_weaknesses": "", "was_revised": false, "final_justification": "", "rebuttal": "", "claims_and_evidence": "", "methods_and_evaluation_criteria": "", "theoretical_claims": "", "experimental_designs_or_analyses": "", "relation_to_broader_scientific_literature": "", "essential_references_not_discussed": "", "other_strengths_and_weaknesses": "", "other_comments_or_suggestions": "", "questions_for_authors": "", "summary_of_paper": "", "summary_of_recommendation": "", "technical_quality": "", "clarity_of_presentation": "", "potential_impact": "", "robotics_focus": "", "quality_of_limitations": "", "questions_for_rebuttal": "", "reasons_to_accept": "", "reasons_to_reject": "", "questions_to_authors": "", "main_review": "", "summary_of_the_paper": "", "summary_of_the_review": "", "strength_and_weaknesses": "", "limitations_and_societal_impact": "", "review_text": "This paper tries to solve the protein-legend binding prediction problem in the computational biology field. It uses the learned embedding for protein and legend, separately, from two published papers. Then those two embeddings were inputted to another deep learning model, performing the final prediction. Tested on one dataset, it shows the proposed method can outperform the other baseline methods.\n\nThe paper should be rejected for the following reasons:\n1. The idea of the paper is not interesting and novel enough. It only used the results from two published papers and then applied another deep learning model on them. The novelty of the paper is limited.\n2. The experiment part is not that comprehensive. It indeed performs enough ablation studies. However, all the legendary methods in the computational biology field are not included in the comparison. \n3. The experiments are only performed on one dataset. Usually, for application papers, the experiments should be performed against at least 2 datasets to avoid bias.\n4. The discussion part is not well-developed. For the paper which focuses on only one task, the more in-depth discussion is expected beyond the simple discussion of the performance. For example, the authors may try to explain the result: why the model used embedding from unsupervised learning is better than the hand-crafted features. Since they shared the same model, the unsupervised embedding should contain more information. Then, what is the additional information? \n\n\nSome further questions and comments:\n1. What's the sequence similarity of the 1226 proteins?\n2. Can the model generalize well to a completely new protein? \n3. What's the detailed performance of the model on proteins belonging to different families? \n4. I guess if the authors check the detailed performance, they will find nonuniform performance across different proteins. I think the authors can also further investigate that.\n5. Can the authors train the embedding model as well as the classification model in an end-to-end fashion? This can be more interesting.\n6. One big problem of the assay data is that it would not be able to provide the structure information of the interaction between the protein and the legend. Usually, it is a very important piece of information for the biology people. The computational methods based on the assay data will also inherit the flaw. ", "extra_scores": {"experience_assessment": "I have published one or two papers in this area.", "review_assessment:_thoroughness_in_paper_reading": "I read the paper at least twice and used my best judgement in assessing the paper.", "review_assessment:_checking_correctness_of_experiments": "I carefully checked the experiments.", "review_assessment:_checking_correctness_of_derivations_and_theory": "I carefully checked the derivations and theory."}, "extra_text": {}}, {"review_id": "BkxnneP9cS", "reviewer": "AnonReviewer4", "summary": "", "questions": "", "limitations": "", "rating": 3, "confidence": null, "soundness": null, "presentation": null, "contribution": null, "strengths": "", "weaknesses": "", "quality": null, "clarity": null, "significance": null, "originality": null, "strengths_and_weaknesses": "", "was_revised": false, "final_justification": "", "rebuttal": "", "claims_and_evidence": "", "methods_and_evaluation_criteria": "", "theoretical_claims": "", "experimental_designs_or_analyses": "", "relation_to_broader_scientific_literature": "", "essential_references_not_discussed": "", "other_strengths_and_weaknesses": "", "other_comments_or_suggestions": "", "questions_for_authors": "", "summary_of_paper": "", "summary_of_recommendation": "", "technical_quality": "", "clarity_of_presentation": "", "potential_impact": "", "robotics_focus": "", "quality_of_limitations": "", "questions_for_rebuttal": "", "reasons_to_accept": "", "reasons_to_reject": "", "questions_to_authors": "", "main_review": "", "summary_of_the_paper": "", "summary_of_the_review": "", "strength_and_weaknesses": "", "limitations_and_societal_impact": "", "review_text": "The authors present a model with state-of-the-art performance for predicting protein-ligand affinity and provide a thorough set of benchmarks to illustrate the superiority of combining learned low-dimensional embedding representations  of both ligands and proteins. The authors then show that these learned representations are more powerful than handcrafted features such as circular fingerprints, etc. when combined into a model that jointly takes as input both the ligand and protein.\n\nI originally suggested to accept the paper, but agree with the other reviewers that the novelty of the work in this paper likely doesn't meet the bar for acceptance given that the most significant contributions of this paper are around combining good ideas from other papers without much additional novelty.\n\nMajor comments\n\nUnless I'm misunderstanding the naming conventions used in Table 1, it seems like an omission not to include the performance of DeepPCM+HP+HC in Table 1 to more fully decouple the performance due to the DeepPCM architecture versus the contribution due to using both unsupervised descriptors in combination.\n\nI might expect the performance of the DeepPCM + HP + HC model (not currently shown unless I'm missing it) to exceed the performance of the NIB + HP + HC model based upon the reasoning given in the discussion (i.e., usefulness of joint input training), even if the individual representations were inferior to the unsupervised counterparts.\n\nSince the primary point of the paper is to illustrate the power of combining the unsupervised representations, I'm surprised the aforementioned performance comparison is not prominent. That is, the performance comparison of DeepPCM+HP+HC versus DeepPCM+UP+UC seems like a very central quantity to present and discuss, but appears to be missing currently.\n\n\nMinor comments\n\nTable 1 was a bit confusing to me at first, because it appears that UD = UP + UC, and HD = HP + HC, but this wasn't obvious to me initially; I'd change the NIB rows to be NIB + HP + HC and NIB + UP + UC, and then you don't even need to define the UD and HD acronyms, which simplifies the table's cognitive load for me and also makes the relationship between the DeepPCM variants more obvious.\n\n> \"On the low-coverage-split, we also find that our method significantly outperforms the benchmark.\"\n\nIt would be good to add the %improvement inline here to parallel the other dataset splits listed just before so that you can directly compare the magnitudes.\n\n> \"using unsupervised-learned descriptors than when using handcrafted descriptors\"\n\nWould be more compelling if you added the DeepPCM + HC + HP performance to Table 1.\n\n> \"All hyperparameter optimization of our model was performed on the temporal split\"\n\nI think it would improve the paper if the extent to which various architecture choices were optimized over could be included as well; for example, which types, layer sizes, and depths of network architectures were considered in the hyperparam tuning, and any accompanying justification for these design choices.\n", "extra_scores": {"experience_assessment": "I have published in this field for several years.", "review_assessment:_checking_correctness_of_experiments": "I carefully checked the experiments.", "review_assessment:_thoroughness_in_paper_reading": "I read the paper thoroughly.", "review_assessment:_checking_correctness_of_derivations_and_theory": "N/A"}, "extra_text": {}}]

Author rebuttal:

Meta-review: This paper uses unsupervised learning to create useful representations to improve the performance of models in predicting protein-ligand binding. After reviewers had time to consider each other's comments, there was consensus that the current work is too lacking in novelty on the modeling side to warrant publication in ICLR. Additionally, current experiments are lacking comparisons with important baselines. The work in its current form may be better suited for a domain journal. 
Decision: Reject