Abstract
Modeling the conformational heterogeneity of protein-small molecule interactions is important for understanding natural systems and evaluating designed systems but remains an outstanding challenge. We reasoned that while residue-level descriptions of biomolecules are efficient for de novo structure prediction, for probing heterogeneity of interactions with small molecules in the folded state, an entirely atomic-level description could have advantages in speed and generality. We developed a graph neural network called PLACER (protein-ligand atomistic conformational ensemble resolver) trained to recapitulate correct atomic positions from partially corrupted input structures from the Cambridge Structural Database and the Protein Data Bank; the nodes of the graph are the atoms in the system. PLACER accurately generates structures of diverse organic small molecules given knowledge of their atom composition and bonding. When given a description of the larger protein context, it builds up structures of small molecules and protein side chains for protein-small molecule docking. Because PLACER is rapid and stochastic, ensembles of predictions can be readily generated to map conformational heterogeneity. In enzyme design efforts described here and elsewhere, we find that using PLACER to assess the accuracy and preorganization of the designed active sites results in higher success rates and higher activities; we obtain a preorganized retroaldolase with a k(cat)/K(M) of 11,000 M(-1)min(-1), considerably higher than any pre-deep learning design for this reaction. We anticipate that PLACER will be widely useful for rapidly generating conformational ensembles of small molecule and small molecule-protein systems and for designing higher activity preorganized enzymes.