# Predictor-Guided Latent Space Codon Optimization for Maximizing Protein Expression

arXiv: https://arxiv.org/abs/2610.03098 · HTML: https://mlsanity.com/paper/2610.03098/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 19 of its 48 references that are in the map.
- First posted on arXiv 2 Oct 2026.

## Builds on (most cited first, 19 of 19)

- [BERT: Pre-training of Deep Bidirectional Transformers for Language Understanding](https://mlsanity.com/paper/1810.04805/) (2018)
- [RoFormer: Enhanced Transformer with Rotary Position Embedding](https://mlsanity.com/paper/2104.09864/) (2021)
- [Simple and Scalable Predictive Uncertainty Estimation using Deep Ensembles](https://mlsanity.com/paper/1612.01474/) (2016)
- [Automatic chemical design using a data-driven continuous representation of molecules](https://mlsanity.com/paper/1610.02415/) (2016)
- [Smarter, Better, Faster, Longer: A Modern Bidirectional Encoder for Fast, Memory Efficient, and Long Context Finetuning and Inference](https://mlsanity.com/paper/2412.13663/) (2024)
- [Protein Design with Guided Discrete Diffusion](https://mlsanity.com/paper/2305.20009/) (2023)
- [Bayesian Optimization is Superior to Random Search for Machine Learning Hyperparameter Tuning: Analysis of the Black-Box Optimization Challenge 2020](https://mlsanity.com/paper/2104.10201/) (2021)
- [Sample-Efficient Optimization in the Latent Space of Deep Generative Models via Weighted Retraining](https://mlsanity.com/paper/2006.09191/) (2020)
- [Conditioning by adaptive sampling for robust design](https://mlsanity.com/paper/1901.10060/) (2019)
- [Accelerating Bayesian Optimization for Biological Sequence Design with Denoising Autoencoders](https://mlsanity.com/paper/2203.12742/) (2022)
- [Design-Bench: Benchmarks for Data-Driven Offline Model-Based Optimization](https://mlsanity.com/paper/2202.08450/) (2022)
- [Conservative Objective Models for Effective Offline Model-Based Optimization](https://mlsanity.com/paper/2107.06882/) (2021)
- [Iterative Refinement Graph Neural Network for Antibody Sequence-Structure Co-design](https://mlsanity.com/paper/2110.04624/) (2021)
- [Design by adaptive sampling](https://mlsanity.com/paper/1810.03714/) (2018)
- [Offline Model-Based Optimization: Comprehensive Review](https://mlsanity.com/paper/2503.17286/) (2025)
- [VarMAE: Pre-training of Variational Masked Autoencoder for Domain-adaptive Language Understanding](https://mlsanity.com/paper/2211.00430/) (2022)
- [Unifying Likelihood-free Inference with Black-box Optimization and Beyond](https://mlsanity.com/paper/2110.03372/) (2021)
- [Bayesian Optimization of Antibodies Informed by a Generative Model of Evolving Sequences](https://mlsanity.com/paper/2412.07763/) (2024)
- [HELM: Hierarchical Encoding for mRNA Language Modeling](https://mlsanity.com/paper/2410.12459/) (2024)

## Abstract (arXiv)

Codon optimization, the process of selecting synonymous codons to improve mRNA translation efficiency and protein expression, is central to therapeutic protein production and mRNA vaccines, yet it remains a hard problem. The design space is discrete and combinatorially large, precluding gradient-based methods, and existing tools rely on heuristic proxies (e.g., Codon Adaptation Index or GC-content) that poorly capture true expression. We introduce Latent-Space Codon Optimization (LSCO), which recasts this discrete problem as a continuous one by mapping sequences into the latent space of a pretrained mRNA language model, enabling efficient gradient-based search. LSCO combines four components: a data-driven expression objective from an uncertainty-aware predictor, a Minimum-Free-Energy regularizer for structural stability, a naturalness prior from a protein-to-codon back-translation model, and constrained decoding for protein fidelity. On a real-world, wet-lab antibody expression dataset, LSCO outperforms simple frequency-based, as well as modern deep generative baselines in predicted expression, while retaining suitable biophysical properties.