Codon language models offer a promising framework for modeling protein-coding DNA sequences, yet current approaches often conflate codon usage with amino acid semantics, limiting their ability to capture DNA-level biology. We introduce SynCodonLM, a codon language model that enforces a biologically grounded constraint: masked codons are only predicted from synonymous options, guided by the known protein sequence. This design disentangles codon-level from protein-level semantics, enabling the model to learn nucleotide-specific patterns. The constraint is implemented by masking non-synonymous codons from the prediction space prior to softmax. Unlike existing models, which cluster codons by amino acid identity, SynCodonLM clusters by nucleotide properties, revealing structure aligned with DNA-level biology. Furthermore, SynCodonLM outperforms existing models on six of seven benchmarks sensitive to DNA-level features, including messenger RNA and protein expression. Our approach advances domain-specific representation learning and opens avenues for sequence design in synthetic biology, as well as deeper insights into diverse bioprocesses.
Heuschkel et al. (Sat,) studied this question.