Proteins are the molecular machines of all living cells and have been exploited for use in many applications, including therapeutics and industrial catalysts. To overcome the limitations of naturally occurring proteins, protein engineering is used to improve protein characteristics such as stability and functionality. In a new study, researchers demonstrate a machine learning algorithm that accelerates the protein engineering process. The study is reported in the journal Nature Communications. Machine learning algorithms assist in protein engineering by reducing the experimental burden of methods such as directed evolution, which involves multiple rounds of mutagenesis and high-throughput screening.

Machine learning has been increasingly used for protein engineering. However, because the general sequence contexts they capture are not specific to the protein being engineered, the accuracy of existing machine learning algorithms is rather limited. Here, we report ECNet (evolutionary context-integrated neural network), a deep-learning algorithm that exploits evolutionary contexts to predict functional fitness for protein engineering. This algorithm integrates local evolutionary context from homologous sequences that explicitly model residue-residue epistasis for the protein of interest with the global evolutionary context that encodes rich semantic and structural features from the enormous protein sequence universe. As such, it enables accurate mapping from sequence to function and provides generalization from low-order mutants to higher-order mutants. We show that ECNet predicts the sequence-function relationship more accurately as compared to existing machine learning algorithms by using ~50 deep mutational scanning and random mutagenesis datasets. Moreover, we used ECNet to guide the engineering of TEM-1 β-lactamase and identified variants with improved ampicillin resistance with high success rates. Protein engineering is an active area of research in which machine learning has proven quite powerful. Here, the authors present a deep learning method that integrates both general and protein-specific sequence representations to improve the engineering of one’s protein of interest.

Inter-agent communication can significantly increase performance in multi-agent tasks that require co-ordination to achieve a shared goal. Prior work has shown that it is possible to learn inter-agent communication protocols using multi-agent reinforcement learning and message-passing network architectures. However, these models use an unconstrained broadcast communication model, in which an agent communicates with all other agents at every step, even when the task does not require it. In real-world applications, where communication may be limited by system constraints like bandwidth, power and network capacity, one might need to reduce the number of messages that are sent. In this work, we explore a simple method of minimizing communication while maximizing performance in multi-task learning: simultaneously optimizing a task-specific objective and a communication penalty. We show that the objectives can be optimized using Reinforce and the Gumbel-Softmax reparameterization. We introduce two techniques to stabilize training: 50% training and message forwarding. Training with the communication penalty on only 50% of the episodes prevents our models from turning off their outgoing messages. Second, repeating messages received previously helps models retain information, and further improves performance. With these techniques, we show that we can reduce communication by 75% with no loss of performance.