arXiv:2603.27526v2 Announce Type: replace

Abstract: Protein fitness optimization is a discrete search problem, and the representation used for prediction also determines the neighborhood graph traversed by an optimizer. We introduce Q-BioLat, a framework that maps pretrained protein-language-model embeddings to compact binary codes and fits a quadratic unconstrained binary optimization (QUBO) surrogate with unary and pairwise latent interactions. Our central contribution is an optimization-aware view of representation: binary encodings that are similar in pointwise predictive accuracy can induce different Hamming neighborhoods, local optima, and search trajectories. We formalize when a recoding is only a Hamming-isometric reparameterization and give a constructive example showing that exact pointwise agreement does not imply optimization equivalence.

We study experimentally measured GFP and AAV fitness landscapes from ProteinGym. The internal QUBO surrogate is evaluated against labels withheld from QUBO fitting. A conservative retrieval analysis maps optimized codes to measured variants and reports their experimental fitness, while neural decoding of potentially unmeasured sequences is evaluated separately with an experiment-trained sequence surrogate and is interpreted only as model-based candidate prioritization. Across the reported comparisons, PCA followed by per-coordinate median thresholding yields a more balanced and decodable binary space than the post-hoc-zero-threshold AE/VAE baselines, despite the latter's low continuous reconstruction error. In the measured-library retrieval analysis, simulated annealing, genetic algorithms, and greedy hill climbing frequently return high-percentile variants; decoded candidates are reported separately using surrogate-predicted scores.