Accurate estimation of mutational effects on protein-protein binding energies is an open problem with applications in structural biology and therapeutic design. Several deep learning predictors for this task have been proposed, but, presumably due to the scarcity of binding data, these methods underperform computationally expensive estimates based on empirical force fields. In response, we propose a transfer-learning approach that leverages advances in protein sequence modeling and folding stability prediction for this task. The key idea is to parameterize the binding energy as the difference between the folding energy of the protein complex and the sum of the folding energies of its binding partners. We show that using a pre-trained inverse-folding model as a proxy for folding energy provides strong zero-shot performance, and can be fine-tuned with (1) copious folding energy measurements and (2) more limited binding energy measurements. The resulting predictor, StaB-ddG, is the first deep learning predictor to match the accuracy of the state-of-the-art empirical force-field method FoldX, while offering an over 1,000x speed-up.

Accurate blind docking has the potential to lead to new biological breakthroughs, but for this promise to be realized, docking methods must generalize well across the proteome. Existing benchmarks, however, fail to rigorously assess generalizability. Therefore, we develop DockGen, a new benchmark based on the ligand-binding domains of proteins, and we show that existing machine learning-based docking models have very weak generalization abilities. We carefully analyze the scaling laws of ML-based docking and show that, by scaling data and model size, as well as integrating synthetic data strategies, we are able to significantly increase the generalization capacity and set new state-of-the-art performance across benchmarks. Further, we propose Confidence Bootstrapping, a new training paradigm that solely relies on the interaction between diffusion and confidence models and exploits the multi-resolution generation process of diffusion models. We demonstrate that Confidence Bootstrapping significantly improves the ability of ML-based docking methods to dock to unseen protein classes, edging closer to accurate and generalizable blind docking methods.

Actor frameworks and similar reactive programming techniques are widely used for building concurrent systems. They promise to be efficient and scale well to a large number of cores or nodes in a distributed system. However, they also expose programmers to nondeterminism, which often makes implementations hard to understand, debug, and test. The recently proposed reactor model is a promising alternative that enables deterministic concurrency. In this article, we present an efficient, parallel implementation of reactors and demonstrate that the determinacy of reactors does not imply a loss in performance. To show this, we evaluate Lingua Franca (LF), a reactor-oriented coordination language. LF equips mainstream programming languages with a deterministic concurrency model that automatically takes advantage of opportunities to exploit parallelism. Our implementation of the Savina benchmark suite demonstrates that, in terms of execution time, the runtime performance of LF programs even exceeds popular and highly optimized actor frameworks. We compare against Akka and CAF, which LF outperforms by 1.86× and 1.42×, respectively.