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Blazing-fast, high-accuracy drug-protein docking with EquiBind Geometric Deep Learning

This week we discuss a new paper from the creators and authors of EquiDock [see our related blog on EquiDock that explores “Independent SE[3] Equivariant Models for End-to-End Rigid Docking”].

Today’s discussion relates to EQUIBIND: Geometric Deep Learning for Drug Binding Structure Prediction EquiBind differs from EquiDock in its flexible ligand modeling. Whereas EquiDock performs rigid protein-protein docking, EquiBind allows for ligand flexibility.

In the simplest sense, EquiBind shares the same core algorithm as EquiDock but uses it for drug protein docking. EquiBind predicts the binding location, pose, and orientation of the drug in a single pass, 100 times faster than the next fastest method, and with mean RMSD error of nearly half the error of the next most-accurate method.

docked_ligand

Left: Backbone of 5HMV [blue] and 1BHZ [tan]. Right: Backbone and side chains of 5HMV [blue] and 1BHZ [tan]. The low-resolution structure matches the correct backbone but fails to accurately predict side chains [see misaligned side chains at the top of the aligned structures].

Here’s a recap from our previous blog post about the neural network architecture that EquiBind uses:

  1. The network takes as input protein coordinates and coordinates of a random ligand conformer [X, X’].
  2. t constructs a graph and performs equivariant coordinate updates to transform [X, X’] into [Z, Z’], then uses an attention mechanism to predict “keypoints” [Y, Y’] – midpoints between the ligand and protein atoms at the binding site – for both the ligand and the protein.
  3. The network uses the singular value decomposition [SVD] to find the roto-translation that aligns the two sets of predicted keypoints [Y, Y’] and applies that roto-translation to all ligand coordinates [X’].
  4. The loss is calculated as the mean-squared error between the predicted ligand coordinates and the true ligand coordinates.

Other terms in this loss are discussed in the previous blog post and the EquiDock paper.

 

Flexible Ligand Modeling

EquiBind differs from EquiDock in its flexible ligand modeling. Whereas EquiDock performs rigid protein-protein docking, EquiBind allows for ligand flexibility.

The authors offer several possible approaches for modeling this flexibility, but their best approach is to apply a post-prediction correction [C, C’] to match the transformed coordinates [Z, Z’]. They do this in a way that respects physical constraints, namely, preserving bond lengths and angles. To do so, they search for a set of coordinates that maximizes the following formula, subject to the constraint:

 

maximize_formula

            

 

constraint

The function to maximize [1] says that it is necessary to find the coordinates that maximize cosine similarity to the transformed coordinates.

The constraint in equation [2] essentially says that, given a change in one torsion angle across a rotatable bond, other torsion angles across that bond will change accordingly. This prevents the maximization of equation [1] while changing bond angles for other atoms around that bond.

This constraint is illustrated in figure 1:

figure_1Newman projection of butane. The constraint in Equation [1] says that for any torsion angle, A = [B + C + D] mod 2π.

The authors prove a closed-form solution to this maximization problem. This solution is differentiable, allowing for loss to be computed as a function of this “nearest physically plausible conformer to Z”.

 

Superior “Blind” Docking

The results are impressive. EquiBind achieves a centroid RMSD of 5.6, with the next-best competitor achieving 11.4. This means that it performs “blind” docking [finding the docking site] far better than competitors. Its aligned RMSD of 2.6 matches the best competitor [also 2.6], which means that although it finds the docking site well, it does not find a superior conformer. However, it does this 100x faster than the next fastest model, and 500x faster than the next most-accurate model.

EquiBind is not without limitations. While this model accounts for several known physical constraints of drug-protein docking, it does not account for flexibility of the protein during ligand docking. This is a common, well-known phenomenon in ligand-protein docking; see for example, PDB 1ANF with maltose bound and unbound. EquiBind likely avoids this case because there are known difficulties with modeling protein flexibility about rotatable bonds the lever-arm effect. But accurate drug-protein binding should account for protein deformation. The model also does not explicitly model protein side chains.

Complimentary Deep Learning Tools

Limitations aside, the speed and accuracy of EquiBind should make it the de facto docking tool for fast docking and high-throughput virtual screening of drug libraries. The authors estimate that their tool will function on the scale of hundreds of millions of molecules.

Used in combination with other types of interaction networks, EquiDock and EquiBind protein-protein interaction networks can be mined for new scientific discoveries about biochemical pathways, biochemical causes of disease, causes of drug toxicity, and more.

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