Efficient Protein Optimization via Structure-aware Hamiltonian Dynamics

The ability to engineer optimized protein variants has transformative potential for biotechnology and medicine. Prior sequence-based optimization methods struggle with the high-dimensional complexities due to the epistasis effect and the disregard for structural constraints. To address this, we propose HADES, a Bayesian optimization method utilizing Hamiltonian dynamics to efficiently sample from a structure-aware approximated posterior. Leveraging momentum and uncertainty in the simulated physical movements, HADES enables rapid transition of proposals toward promising areas. A position discretization procedure is introduced to propose discrete protein sequences from such continuous state system. The posterior surrogate is powered by a two-stage encoder-decoder framework to determine the structure and function relationships between mutant neighbors, consequently learning a smoothed landscape to sample from. Extensive experiments demonstrate that our method outperforms state-of-the-art baselines in in-silico evaluations across most metrics. Remarkably, our approach offers a unique advantage by leveraging the mutual constraints between protein structure and sequence, facilitating the design of protein sequences with similar structures and optimized properties.