Biocatalysis is a promising approach to sustainably synthesize pharmaceuticals, complex natural products, and commodity chemicals at scale. However, the adoption of biocatalysis is limited by our ability to select enzymes that will catalyze their nat
ural chemical transformation on non-natural substrates. While machine learning and in silico directed evolution are well-posed for this predictive modeling challenge, efforts to date have primarily aimed to increase activity against a single known substrate, rather than to identify enzymes capable of acting on new substrates of interest. To address this need, we curate 6 different high-quality enzyme family screens from the literature that each measure multiple enzymes against multiple substrates. We compare machine learning-based compound-protein interaction (CPI) modeling approaches from the literature used for predicting drug-target interactions. Surprisingly, comparing these interaction-based models against collections of independent (single task) enzyme-only or substrate-only models reveals that current CPI approaches are incapable of learning interactions between compounds and proteins in the current family level data regime. We further validate this observation by demonstrating that our no-interaction baseline can outperform CPI-based models from the literature used to guide the discovery of kinase inhibitors. Given the high performance of non-interaction based models, we introduce a new structure-based strategy for pooling residue representations across a protein sequence. Altogether, this work motivates a principled path forward in order to build and evaluate meaningful predictive models for biocatalysis and other drug discovery applications.
Machine-learning models that learn from data to predict how protein sequence encodes function are emerging as a useful protein engineering tool. However, when using these models to suggest new protein designs, one must deal with the vast combinatoria
l complexity of protein sequences. Here, we review how to use a sequence-to-function machine-learning surrogate model to select sequences for experimental measurement. First, we discuss how to select sequences through a single round of machine-learning optimization. Then, we discuss sequential optimization, where the goal is to discover optimized sequences and improve the model across multiple rounds of training, optimization, and experimental measurement.
