Paper: DockGame: Cooperative Games for Multimeric Rigid Protein Docking (ICLR-2024)

Reviewer comment (Theory):
The game-theoretic approach is not well enough formalised. This makes it hard to judge to what extend the game-theoretic view on the multimeric rigid protein docking problem helps in the understanding of the problem.

Author response:
**Introduction, Q1**: 
Thank you for the suggestion. We are happy to emphasize this point more in the updated version of the paper, and more formally connect the notion of equilibria to assembly structures.

Reviewer comment (Theory):
Some of the modelling choices, especially the use of a surrogate model for the molecular potential, is not sufficiently motivate. At this time, I am unsure why the surrogate model is needed.

Author response:
**Method, Q4**: There are multiple reasons for this: 

- Rosetta has limited support for any computations on GPU and their docking protocols are only designed for binary docking. Any extension to multimeric docking would require writing a custom protocol that follows the traditional paradigms of pairwise docking + combinatorial assembly, which is precisely the disadvantage we highlighted in the Introduction. This would also make multimeric docking very slow, as evidenced by the time taken by MultiLZerd for the same multimeric docking problem (Table 1). In contrast, DockGame can run on GPU and has much faster runtimes.

- Diffusion models can additionally be augmented with a guidance term that can be used to steer the diffusion towards targets of interest. The potential network thus learnt in Section 4.2 can be used as additional guidance term. This is easy from an implementation perspective when all the computations can be done on GPU, which is not possible with Rosetta or other docking protocols.

- While we use the PyRosetta energetics in this paper to learn an approximation, we could just as easily use a pretrained property predictor as the game potential f. The goal was to showcase a proof-of-concept for learning the game potential, and using it to compute equilibria rather than the *choice* of the functions used to generate supervised data.

Reviewer comment (Writing):
One question that popped up in my mind several times while reading the abstract is the difference between the *game potential* and the *molecular potential* that defines, to some extend, the possible configurations in a physical sense. I believe that this is what the paper refers to with "physics-based energy function", but this was slightly confusing.

Author response:
**Abstract, Q2** :Thank you for the comment. 

The term molecular potential is typically used to refer to the function that characterizes the energy landscape of different molecular configurations.

The game potential, on the other hand, is not just restricted to energetics. While we do agree that in the context of the supervised learning section of the paper, they are the same, in general this need not be the case. The game potential could just as well represent a function that characterizes some other property such as toxicity or solubility for instance, without any modifications to the strategy to compute equilibria.

Our intention while writing was to not show how the molecular potential resembles the game potential, but instead to map out different components used in defining a game to appropriate aspects of the rigid multimeric docking problem.

Reviewer comment (Theory):
The paper does not properly set out the relation between the potential function, in game theoretic sense, and the molecular potential. This issue appears in the introduction where the paper mentions that the "final assembly structure(s) constitute stable equilibria". The paper should relate the stable equilibria, in the game theoretic sense, with meta-stable states of the protein-protein complexes.

Author response:
**Preliminaries and Background, Q3**: First, the game-theoretic aspect of the paper is not just concerned with the presence of an underlying potential, but also on the strategy used for computing equilibria when given such a potential and appropriate action spaces. Since the action spaces are continuous, gradient-based methods for computing equilibria can be applied. The game-theoretic perspective, thus allows to formulate multimeric docking as a gradient-based optimization problem instead of the traditional combinatorial assembly paradigm. 

Second, in the context of multimeric docking, we do not have access to the underlying potential (or payoffs in case of general-sum games) but only equilibria samples. Thus, to compute equilibria, we need to either specify or learn an appropriate potential. In the multi-agent literature, this is referred to as the inverse multi-agent RL problem (the RL is not applicable in our setting). Both approaches are designed to specifically tackle this problem of inferring the potential before computing equilibria. 

We do agree that in the context of cooperative games, equilibria correspond to local minima and equilibrium computation is equivalent to minimizing the potential, this does not make the adopted strategies any less game-theoretic. We have also given an example in a later answer for the case of general-sum games, where gradient-based algorithms for equilibrium computation are just as applicable. 

We are however happy to include a justification for why the assembly structures constitute equilibria wrt an appropriate potential, and make a more formal argument in this regard.

Reviewer comment (Novelty):
In the related work, Ketara et al., which introduced the DiffDock-pp method, generates an ensemble of possible complexes. This makes the method very similar to the proposed method in the sense that they both are able to compute multiple equilibria. This similarity should be made more clear in the related work discussion of this work.

Author response:
**Introduction, Q3**: Below we include the relevant statement from the Related Work section:

“The closest related work to ours are (Corso et al., 2023; Ketata et al., 2023), of which our diffusion generative model for the cooperative game can be interpreted as a multi-agent extension.” 

We believe this statement sufficiently captures the intent of the reviewers comment, especially since we do not emphasize the confidence model used in DiffDock-PP to rank samples and actually refer to them as a generative model. 

Second, the diffusion generative model, while an obvious extension of DiffDock-PP, provides a general recipe for defining diffusion models over (continuous) action spaces in cooperative games, connecting diffusion models with the multi-agent community, and allowing either community to benefit from advances in the other.

Third, the connections between sampling in diffusion models and equilibrium computation in (cooperative) games are interesting in their own right. In the multi-agent literature, connections between sampling and equilibrium computation have been explored largely in the context of mean-field games (where one has infinite agents), or games with a large but finite but large number of homogenous agents. 

In contrast, our diffusion model does not place an assumption of the types of players, and provides a general recipe to define diffusion models over the (continuous) action spaces of all players in the cooperative game, when one only has access to equilibria and not the underlying game structure.

Reviewer comment (Theory):
In "Preliminaries and Background", I would like to ask the authors to clarify the cost function / potential introduced in the paragraph titled "Game Theoretic Concepts". From my understanding, a potential function (or as the authors first call it, a cost function) is an abstraction of the payoff function and should really be defined as a function over the current states of the agent. It is possible to define the potential function using sequences of actions or strategies, but this is only possible with a fixed starting state. When introducing the used potential function in section 4.2, it is actually defined over the state space (in the form of protein point clouds), which contradicts the earlier background discussion. This confusion is a breaking issue at the moment and should be clarified.

Author response:
**Preliminaries and Background, Q2**:  In the multi-agent and game-theory communities, the payoff function for each player in the game depends on the actions (or strategies) adopted by all players, and we stick to the same definition. However, there are some subtleties that apply when working with point clouds in Euclidean spaces with rotations and translations as actions for each player. 

First, both rotations and translations are **groups**, and applying a rotation and translation to an element in the Euclidean space corresponds to the formal notion of **group action**. The notion of **group action** is what allows us to forget about the fixed starting state, as can be seen from the following:

Let $x$ be a fixed starting state, and let $R_a, R_b$ be rotations, whose action on $x$ results in $x_a, $x_b$ respectively. As the set of rotations form a group, there exists a rotation $R_bR_a^-1$, which when applied to $x_a$ corresponds results in $x_b$, since it first reverses $x_a$ back to $x$, and then applies $R_b$ to $x$. Thus the group action of $R_b$ on $x$ produces the same result as $R_bR_a^-1$ on $x_a$, allowing us to “forget” the location of the starting state $x$. 

Second, providing the full 3D structure of the proteins, rather than abstract elements from the action space for each player, allows the model to reason about physical interactions and better generalize to unseen assemblies. This viewpoint is not new, and was also adopted in DiffDock & DiffDock-PP.

Reviewer comment (Theory):
The Game-Theoretic Concepts section highlights that the game-theoretic aspects of the proposed method are not very strong. As it stands, the paper does not relate the potential function, in the game theoretic sense, to the molecular potential and does thus not show that the stable equilibria, in the game-theoretic sense, are related to local minima of the molecular potential. The game theory aspect could be removed completely by clearly stating that the potential f is a learned approximation of the true molecular potential.

Author response:
**Preliminaries and Background, Q3**: First, the game-theoretic aspect of the paper is not just concerned with the presence of an underlying potential, but also on the strategy used for computing equilibria when given such a potential and appropriate action spaces. Since the action spaces are continuous, gradient-based methods for computing equilibria can be applied. The game-theoretic perspective, thus allows to formulate multimeric docking as a gradient-based optimization problem instead of the traditional combinatorial assembly paradigm. 

Second, in the context of multimeric docking, we do not have access to the underlying potential (or payoffs in case of general-sum games) but only equilibria samples. Thus, to compute equilibria, we need to either specify or learn an appropriate potential. In the multi-agent literature, this is referred to as the inverse multi-agent RL problem (the RL is not applicable in our setting). Both approaches are designed to specifically tackle this problem of inferring the potential before computing equilibria. 

We do agree that in the context of cooperative games, equilibria correspond to local minima and equilibrium computation is equivalent to minimizing the potential, this does not make the adopted strategies any less game-theoretic. We have also given an example in a later answer for the case of general-sum games, where gradient-based algorithms for equilibrium computation are just as applicable. 

We are however happy to include a justification for why the assembly structures constitute equilibria wrt an appropriate potential, and make a more formal argument in this regard.

Reviewer comment (Writing):
When discussing multimeric protein docking, the authors should clarify that they are referring to the *rigid* version of this problem. In the current version of the paper this is not always clarified.

Author response:
**Method, Q1**: Thanks, we have tried our best to ensure this is mentioned in all the relevant places but are happy to include it in other parts of the paper accordingly.

Reviewer comment (Novelty):
When stating "Previous models tackle this [..]" the paper should include citations to the specific previous methods that do this.

Author response:
**Method, Q2**: Thank you, we will include relevant citations while referring to previous methods in the text.

Reviewer comment (Theory):
When the paper mentions "game equilibria, i.e. stable outcomes from which no agent has an incentive to deviate", it should justify that this is a correct objective to aim for by showing, formally, that these game equilibria are located at local minima of the molecular potential landscape.

Author response:
**Method, Q3**: Thank you, we will include a more formal characterization of equilibria and a justification of why the objective is an appropriate one to aim for in the updated version(s) of the paper.

Reviewer comment (Experiments):
In section 4.1 the authors state "we do not have access to the underlying game potential f". While this is true to some extent (using DFT at this scale is not possible), we do have very good approximations available in the form of empirical force fields. This misunderstanding becomes clearer in section 4.2 where the authors introduce gradient-based learning with surrogate potentials. It is unclear why the authors require the training of a surrogate model instead of using the energy minimisation functionality from Rosetta to find the equilibria for the randomly initialised proteins. This is a breaking issue and should be clarified.

Author response:
**Method, Q4**: There are multiple reasons for this: 

- Rosetta has limited support for any computations on GPU and their docking protocols are only designed for binary docking. Any extension to multimeric docking would require writing a custom protocol that follows the traditional paradigms of pairwise docking + combinatorial assembly, which is precisely the disadvantage we highlighted in the Introduction. This would also make multimeric docking very slow, as evidenced by the time taken by MultiLZerd for the same multimeric docking problem (Table 1). In contrast, DockGame can run on GPU and has much faster runtimes.

- Diffusion models can additionally be augmented with a guidance term that can be used to steer the diffusion towards targets of interest. The potential network thus learnt in Section 4.2 can be used as additional guidance term. This is easy from an implementation perspective when all the computations can be done on GPU, which is not possible with Rosetta or other docking protocols.

- While we use the PyRosetta energetics in this paper to learn an approximation, we could just as easily use a pretrained property predictor as the game potential f. The goal was to showcase a proof-of-concept for learning the game potential, and using it to compute equilibria rather than the *choice* of the functions used to generate supervised data.

Reviewer comment (Theory):
A second breaking issue is the formulation of the loss function used to train the surrogate model. While the use of the ranking loss retains relative ordering of the sampled complexes in terms of energy, it does not accurately reflect the gradient of the energy surface. This limits applicability for deriving thermodynamical properties in possible downstream applications due to possible oversampling of high energy complexes. Although deriving thermodynamical properties is not an objective of the paper, this conflicts with a statement in section 4.2's discussion that "$f_\theta$ can also be used beyond equilibrium computation e.g. to characterise the associated energy landscape (...)".

Author response:
**Method, Q6**: We are happy to take the statement regarding $f_{\theta}$ out of the paper. However, we respectfully disagree with the statement on the accuracy of the gradient landscape. The equilibria are computed by taking gradients of the learnt potential function, and as shown in Fig 2(b), the model is able to find assembly structures with low energy according to PyRosetta as the game progresses, so the model is indeed able to learn (in expectation) accurate gradients through pairwise ranking comparisons.

Reviewer comment (Theory):
The statement "in case of general-sum games more sophisticated update rules could be employed [...]" is unclear in how it translates to the problem at hand. The authors should include an example of how the protein docking problem could be defined as a general-sum game. Similarly, it is unclear what the physical realisation of adding penalty terms for each protein would be as discussed in this section.

Author response:
**Method, Q7**: A general-sum game is defined by a different payoff function for each player. In the case of proteins, the payoff could be for instance the common payoff (as is learnt currently), dictating some properties of the assembly (like energetics or other task-specific properties) plus an additional weighted (weighted per protein) penalty term that minimizes the deviation from the native structure. We do note that general-sum games are more applicable in the context where we have both the unbound and bound structures of the proteins, rather than the setting considered here where we only focus on rigid bound structures.

The intuition behind the payoff functions is that the unbound (or native) structures of the protein are stable when said protein is considered in isolation, but this structure might not be optimal when forming the assembly. There is thus a tradeoff between the selfish objective of the protein (maintaining its own structure closer to the native one), and the common cooperative objective of forming an assembly.

A combination of a common cooperative objective with a weighted penalty term provides different payoff functions for each protein, thus constituting the general-sum game formalism.

Reviewer comment (Theory):
In section 4.3 the paper states "An equivalent characterization of the assembly structures is interpreting them as sample(s) from the mode(s) of the Gibbs distribution". This highlights the concern with the game-theoretic framework: the target docked complexes are *exactly* the modes of the Gibbs distribution if f is defined to be the molecular potential.

Author response:
**Method, Q8**: Thank you for the comment. We hope the following rephrasing will help clarify any concerns:

If f is defined as the molecular potential, the corresponding Gibbs distribution has a higher density at assembly structures with lower potentials. When drawing samples from this distribution, we are more likely to observe assembly structures that have higher density. These are the samples over which we learn the diffusion generative model.

Reviewer comment (Writing):
In section 4.4 the paper switches from using $\mathbf{H}$ to $\mathbf{A}$ for referring to the residues features. This switch is confusing and should be clarified, especially since using A for the features conflicts with the notation of the agents' actions.

Author response:
**Method, Q10**: Thank you for pointing this out -- this should indeed be $\textbf{H}$ in section 4.4 and not $\textbf{A}$.

Reviewer comment (Theory):
The architecture definition clarifies that graphs are used to model interactions between both the residues of the same and different proteins. Considering that the paper focuses on *rigid* docking, it is unclear why internal interactions are needed. The authors should clarify their reasoning regarding this.

Author response:
**Method, Q11**: Internal interactions allow residues to reason about their local environments and represent higher-level properties (say a hydrophobic patch on one protein for instance). In combination with external relations, this allows the model to reason about properties important for assembly formation (for e.g. bringing the hydrophobic patches of two proteins closer together so they can be buried in the binary assembly) and predict the rotational and translational scores accordingly. 

Without the use of internal interactions, the model would have a much harder time connecting protein specific properties to assembly properties and model training will be slower.

Reviewer comment (Experiments):
It is unclear whether DIPS was only used for training the model and not for evaluation. In the "Datasets" paragraph the paper mentions "We use the same splits for the DIPS and DB5.5 datasets as Gana et al. for our experiments", but there is no evaluation of the DIPS dataset.

Author response:
**Experiments, Q1**: The DIPS dataset was only used for training, followed by finetuning on the DB5.5 dataset, following the procedure as in Ganea et al. While their goal was to evaluate *binary* docking, we wanted to evaluate *multimeric* docking. The DIPS dataset only consists of 2 protein (chain) examples, while the DB5.5 dataset had examples with multiple chains in the same protein, which allowed us to evaluate our method at the level of multimeric docking.

Reviewer comment (Novelty):
For the comparison with DiffDock-PP, given that a similar manifold diffusion model is used, it is unclear how considerable the difference is between the proposed model and DiffDock-PP and whether that difference explains the difference observed between DockGame-SM and DiffDock-PP.

Author response:
**Experiments, Q2**: For the case of rigid bodies, DockGame can be interpreted as a multi-agent extension of DiffDock-PP. 

From a training procedure, there is no difference on the DIPS dataset since it only has examples with two chains. However, the DB5.5 dataset consists of multi-chain proteins (these proteins are referred to as subassemblies), which can either be evaluated at the binary docking level (treating each subassembly as an individual entity) or multimeric docking (treating each chain as an individual entity).

On the finetuning step for DB5.5, DiffDock-PP is finetuned at the level of binary docking, while DockGame is finetuned at the level of multimeric docking. We hypothesize that the additional improvement comes from the fact that the diffusion model in DockGame is trained to reason about relevant interactions to form subassemblies (by splitting them into constituent chains) while in DiffDock-PP, these subassemblies are left intact.

Reviewer comment (Presentation):
For table 1, due to the large amount of models evaluated, it is hard to compare the differences. It would be beneficial if the authors could highlight the best scores for each metric.

Author response:
**Experiments, Q3**: Thanks, we will incorporate this suggestion. However, a comparison solely based on best scores is not ideal for tasks like multimeric or binary docking, where typically multiple plausible structures exist, but only one is experimentally available.

Reviewer comment (Evaluation):
Also related to table 1, based on the presented standard deviations, it seems like all methods very much overlap in their scores. If the standard deviation refers to the samples in the filtered set of predicted assemblies, it is unclear how that works for the C-RMSD score. The authors should comment on this.

Author response:
**Experiments, Q4**: Standard deviations are computed not only over the samples in the filtered set but also across all DB5.5 test complexes. This is also the case with the “best C-RMSD score” generations.

Reviewer comment (Experiments):
For the TM-Score cutoff of 0.05, it would be good if the paper could comment on how this relates to the identification of the different meta-stable states. If the threshold is set so that all accepted samples are from the same meta-stable state, all accepted samples would be expected to be exactly the same as the only source of stochasticity is the complex initialisation.

Author response:
**Experiments, Q5**: Thank you for the comment. We will clarify this in the paper, supported by an additional analysis of the TM-scores between different generations. The reviewer is correct that all the accepted samples should be from the same meta-stable state (indeed, this is our goal with such a filtering). However, even if structurally similar, such samples still exhibit some differences due to random noise injected at each diffusion step.

Reviewer comment (Novelty):
The motivation appears weak considering existing capabilities in multimeric docking and flexible models, such as Multimer, which have shown outstanding performance. The significance of designing an alternative rigid docking model remains unclear. Additionally, some generative models, like diffdock-pp and foldingdiff, seem straightforward to extend to multimeric docking.

Author response:
Thank you for your comments. We first aim to address the first two weaknesses jointly.

**Motivation of Game-Theoretic Approach**

As we discuss in the general response, the traditional paradigm in multimeric docking is to do pairwise docking between pairs of proteins, and then apply a combinatorial assembly algorithm to generate the final assembly structure. In contrast, the game-theoretic approach explores the combinatorial docking space by using local gradients (local wrt each protein’s actions) of the payoffs for each protein. This has an effect on the runtimes, where a traditional multimeric docking method like MultiLZerd takes about 20h to generate an assembly structure, while DockGame is able to generate a single structure in 4s (GPU vs CPU not withstanding).

The framework can be extended to flexible multimeric docking by defining the protein specific payoff to be the common payoff plus a protein specific penalty term based on structural deviation from the native structure. This additional penalty term would only contribute a marginal to modest increase in runtimes.

AlphaFold-Multimer indeed has great performance on multimeric docking, but is well known to be slow, and the performance degrades as the number of protein chains increases. In contrast, cooperative games, in principle, are more amenable to scalability, and gradient-based equilibrium computation provides an efficient exploration of the combinatorial docking space. Furthermore, one can compute multiple equilibria (either using diffusion models or gradients of potential network) in cooperative games, while AlphaFold-Multimer can only produce a single assembly structure estimate.

**Comparisons to DiffDock-PP & FoldingDiff**

While methods such as DiffDock-PP and FoldingDiff can be extended to the multimeric docking problem, this is something we also acknowledge in the Related Work section of the paper as well - “The closest related work to ours are (Corso et al., 2023; Ketata et al., 2023), of which our diffusion generative model for the cooperative game can be interpreted as a multi-agent extension.”

Reviewer comment (Novelty):
There are some concerns about the contribution. The application of game theory does not introduce any additional benefits to the model design, as the derived diffusion framework and potential network would seemingly exist even without its inclusion.

Author response:
Thank you for your comments. We first aim to address the first two weaknesses jointly.

**Motivation of Game-Theoretic Approach**

As we discuss in the general response, the traditional paradigm in multimeric docking is to do pairwise docking between pairs of proteins, and then apply a combinatorial assembly algorithm to generate the final assembly structure. In contrast, the game-theoretic approach explores the combinatorial docking space by using local gradients (local wrt each protein’s actions) of the payoffs for each protein. This has an effect on the runtimes, where a traditional multimeric docking method like MultiLZerd takes about 20h to generate an assembly structure, while DockGame is able to generate a single structure in 4s (GPU vs CPU not withstanding).

The framework can be extended to flexible multimeric docking by defining the protein specific payoff to be the common payoff plus a protein specific penalty term based on structural deviation from the native structure. This additional penalty term would only contribute a marginal to modest increase in runtimes.

AlphaFold-Multimer indeed has great performance on multimeric docking, but is well known to be slow, and the performance degrades as the number of protein chains increases. In contrast, cooperative games, in principle, are more amenable to scalability, and gradient-based equilibrium computation provides an efficient exploration of the combinatorial docking space. Furthermore, one can compute multiple equilibria (either using diffusion models or gradients of potential network) in cooperative games, while AlphaFold-Multimer can only produce a single assembly structure estimate.

**Comparisons to DiffDock-PP & FoldingDiff**

While methods such as DiffDock-PP and FoldingDiff can be extended to the multimeric docking problem, this is something we also acknowledge in the Related Work section of the paper as well - “The closest related work to ours are (Corso et al., 2023; Ketata et al., 2023), of which our diffusion generative model for the cooperative game can be interpreted as a multi-agent extension.” 

While we agree with the reviewer that game-theory does not provide any additional benefit to the model design (the architectures of the potential network and diffusion model), we wish to clarify that the introduction of game-theory for multimeric docking problem was **not to improve model design**, but provide a **different perspective for approaching the problem**, with advantages and motivation highlighted above.

**Connections between Diffusion Models and Multi-Agent Modeling**

The connections between sampling in diffusion models and equilibrium computation in (cooperative) games are interesting in their own right. In the multi-agent literature, connections between sampling and equilibrium computation have been explored largely in the context of mean-field games (where one has infinite agents), or games with a large but finite but large number of homogenous agents. 

In contrast, our diffusion model does not place an assumption of the types of players, and provides a general recipe to define diffusion models over the (continuous) action spaces of all players in the cooperative game, when one only has access to equilibria and not the underlying game structure. Even if naturally obvious, this provides a connection between diffusion generative models and multi-agent system modeling, allowing for either community to benefit from respective advances.

Reviewer comment (Novelty):
There are confusions about the supervision of the energy function. Regarding the difficulty in learning the Boltzmann distribution, molecular simulation is both time-consuming and resource-intensive. I wonder how many samples are needed to learn potential functions. Besides, the inference process appears to mirror that of standard docking software, involving random sampling, evaluation, and ranking, which typically does not necessitate additional network training. Considering this, the necessity of the proposed potential network is unclear.

Author response:
>There are confusions about the supervision of the energy function...

We use 10 perturbed samples per example to learn the potential function and train our model on 10000 examples from the DIPS dataset. We wish to emphasize that the potential function for only roto-translation perturbations (considered in this work) would be different than the one allowing for structural changes, with the latter being much more difficult to learn. 

Regarding the mirroring of our inference (equilibrium computation) process with those adopted by standard docking software, we wish to clarify some differences:

Traditional *binary* docking software utilize random sampling, evaluation and ranking to generate docked structures. Traditional *multimeric* docking software however utilize a pairwise docking procedure (which builds on traditional binary docking), followed by a combinatorial assembly algorithm. This makes traditional methods like PyRosetta or MultiLZerd very slow, in addition to offering little to no support for GPU. 

In contrast, our inference process only uses randomization at initialization, does not involve any ranking but instead gradient-based updates which are fully supported on the GPU. In particular, as opposed to combinatorial assembly algorithms, our game-theoretic approach explores the combinatorial docking space by using local gradients (local wrt each protein’s actions) of the payoff. As a result, DockGame achieves much faster run-times than traditional multimeric docking methods (Table 1).

Reviewer comment (Novelty):
The separation of the two models within the paper suggests a fragmented approach. There is an inquiry into the possibility of utilizing energy to guide the learning of the diffusion generative model, potentially unifying the two models for a more cohesive structure.

Author response:
>The separation of the two models ...

Thank you for the remark. We developed the two approaches independently but our goal was to eventually unify them using the potential network as a guidance.

Reviewer comment (Experiments):
Experimental results are not convincing enough. The limited size of the DB5.5 dataset raises concerns about the generalizability of the results to larger datasets such as DIPS. Furthermore, the absence of a comparison with HDock, a robust baseline for rigid docking, is notable. The paper also falls short in showcasing significant improvements compared to existing software baselines. The absence of essential ablation studies, such as those involving distance-based penalties, further undermines the strength of the experimental findings.

Author response:
>Experimental results are not convincing enough...

For this work, we stuck to DB5.5 dataset for evaluation because it is the more traditionally used binary docking dataset, but can also support multimeric docking as many proteins are made up of multiple chains. This allowed us to compare DockGame at the level of multimeric docking to other baselines at the level of binary docking, in addition to traditional multimeric docking software like MultiLZerd. 

We outperform MultiLZerd significantly both in terms of runtime and other metrics, and have better median C-RMSDs than all methods except ClusPro, while being two orders of magnitude faster. HDock was left out of comparison because it is well known that their scoring function was fine-tuned on the DB4 dataset, which shares many examples with the DB5 dataset and makes their predictions look overoptimistic. We did not use DIPS for evaluation since the dataset only has examples with two chains while our goal was to evaluate DockGame at the level of multimeric docking.

Reviewer comment (Theory):
The paper mentions the use of game theory, but in my view, the authors initially just use game theory as a narrative tool. The method does not actually involve game theory, which was somewhat disappointing when I read the methods section.

Author response:
The paper mentions the use of game theory, but in my view, the authors initially just use game theory as a narrative tool. The method does not actually involve game theory, which was somewhat disappointing when I read the methods section.

We acknowledge your point of view, but respectfully disagree in this regard. We attempt to clarify this next. 

First, as we discuss in the general response, game theory is not just used as a narrative tool, but the introduced game-theoretic viewpoint is what allows us to view proteins as independent and potentially self-interested entities (in terms of deviations from their own native structures) with individual action spaces.

This is in stark contrast with previous methods, which first apply a pairwise docking and then combinatorial assembly, and allows us to: 1) in principle, to scale efficiently to a large number of proteins and 2) naturally compute multiple plausible equilibria. See general response for a more detailed discussion about such points. 

In terms of methods, both our approaches are tightly bound to game theory. Indeed, in both cases proteins jointly update their strategies based on their local gradients (either coming from the surrogate potential function, or from the score network), which is a commonly used decentralized scheme in multi-agent learning to compute game equilibria. We acknowledge that this can also be viewed as local optimization of the potential function (because we consider a simple potential game), but the two do not coincide in case of more general payoff structures, e.g. when modeling flexible structures.

Reviewer comment (Presentation):
The presentation is not satisfactory.

Author response:
The presentation is not satisfactory.

We appreciate the suggestion, and are happy to make relevant changes in this regard. Could you point to specific parts in the manuscript that would benefit from a change in presentation?

Reviewer comment (Experiments):
In the experimental section, why are there inconsistent assemblies provided by DOCKGAME-E and DOCKGAME-SE (one being 20 and the other 40)? This seems a bit unfair to DOCKGAME-E.

Author response:
In the experimental section, why are there inconsistent assemblies provided by DOCKGAME-E and DOCKGAME-SE (one being 20 and the other 40)? This seems a bit unfair to DOCKGAME-E.

This was purely due to our computational resources being limited when running such experiments. For DockGame-E, our goal was also to compute PyRosetta scores at each game iteration (to generate, e.g. Figure 2), and this required larger runtimes. We are now predicting 40 complexes for both methods in our current experiments.

Reviewer comment (Theory):
Can the proposed method be extended to torsional space?

Author response:
Yes. The proposed method can be extended to the torsional space. However proteins are large graphs, and the modifications of torsional angles can have larger lever-arm effects on the protein structures, which can make training difficult.

Reviewer comment (Evaluation):
I would like to see the results on the DockQ metric.

Author response:
DockQ metric has been developed in the context of binary docking. While the DockQ metric can be extended to multimeric docking by considering all pairs of interfaces in the assembly (and averaging them accordingly), this would imply a different set of comparisons between binary and multimeric docking methods. Our goal with the experiments was to highlight that DockGame can achieve comparable performance to binary docking methods while solving the multimeric docking task, and DockQ metrics would not have assisted in this regard.

Reviewer comment (Experiments):
the major limitation of this paper is experiments. for example, the author filter results by TM-score and C-RMSD. What's performance without any filtering or ranking by model's potential.

Author response:
The reason we operate filtering by TM score, is that DockGame naturally finds multiple plausible types of docked versions (plausible equilibria), while the test data consists of a single docked complex. Thus, to cope with this, we select the subset of generated complexes that are structurally similar to the bound version (as measured by TM score). We will clarify this point further and will add complete metrics distributions.

Reviewer comment (Evaluation):
It's interesting to show the distribution of decoy quality and the sampling efficient.

Author response:
These are both key features of DockGame. Indeed, compared to previous work, DockGame 1) can compute multiple plausible equilibria for each protein and 2) scales favorably with the number of chains. We acknowledge that both these messages were not delivered sufficiently well in our experiments. We will add two additional plots and discussions illustrating these points.

Reviewer comment (Experiments):
although alphafold-multimer already used data in test, i think it's necessary to curate a new small data set from latest PDB. alphafold-multimer is a strong baseline.

Author response:
Thank you for the suggestion. To compare to AlphaFold-Multimer, we would indeed need to curate a different test set from PDB. This would also imply curating an appropriate large training set and retraining our methods.

Reviewer comment (Experiments):
in the section of "Equilibrium Computation via Gradient-Based Learning", filtering decoys by Euclidean distance only could not be sufficient. i am not sure how noisy is the training data if you only use this filter. i guess this heuristic approach could limit the performance of DOCKGAME-E (DOCKGAME-E is worse than DOCKGAME-SM from table 1)

Author response:
The Euclidean distance constraint is *only* an inference-time addition and is not applied to the decoys generated at training time. The decoys are generated at training time for the purpose of learning an (approximate) potential function.

Furthermore, as mentioned in the section, this constraint is added to prevent proteins in the assembly from being far away in the 3D space (this would correspond to protein undocking), which are also equilibria wrt the potential. The distance penalty also contributes to the gradient-based equilibrium computation only if the distances between proteins is greater than the specified threshold. 

The evaluation in Table 1 measures C-RMSD, which will only be lower if the predicted assembly is close in an RMSD sense to the true assembly. Thus the addition of the distance constraint does not limit the performance of the DockGame-SM, since its only function is to discourage proteins to be too far away from each other.

Reviewer comment (Novelty):
missing some key references:  
[1] Bryant, Patrick, et.al. Predicting the structure of large protein complexes using AlphaFold and Monte Carlo tree search  
[2] Yujie Luo, et.al. xTrimoDock: Rigid Protein Docking via Cross-Modal Representation Learning and Spectral Algorithm.  
[3] Ambrosetti, Francesco, et.al. Modeling antibody-antigen complexes by information-driven docking.  
[4] Ghani, Usman, et.al. Improved docking of protein models by a combination of alphafold2 and cluspro

Author response:
Thank you for the pointers. Reference [1] is already in the paper. We will add the remaining references.

Reviewer comment (Experiments):
is this method robust on single's structure? for example, if you use predicted protein structure rather unbound native structure, what's the performance.

Author response:
Currently, DockGame only uses rotations and translations as the action space for each protein. This means we start with the true assembly structure and apply roto-translation perturbations to each protein to learn the underlying game potential. We could indeed start with predicted structures and compute the assembly structure, but the predictions would be way off for examples where the native structure of a protein undergoes larger structural changes in the assembly. 

The current framework would have to be extended to include structure-based penalty terms in the equilibrium computation step to improve the model’s robustness, which we believe is beyond the current technical scope of the paper, and is left to future work.