Papers for
protein design teams
Papers whose findings have a practical use for this group, as judged from the abstract. Open a paper to read what it means in practice.
Surrogate rewards improve steerability of generative models without oracle queries
Steered Not Stirred: Effective Reward Tilting using Surrogate Reward Mixing
Abstract: Continuous-time generative models, from diffusion models, flow matching, and now flow maps, owe their practical value to high-fidelity generation and steerability. In many applications, a ground-truth latent ``oracle'' reward $R^*$ is unavailable or expensive to evaluate, e.g., human judgments or experimental measurements. Although the oracle reward is not directly observable, it can often be approximated through multiple cheaper surrogates that, individually, provide incomplete characterizations but collectively reveal substantial information about the downstream task. In this paper, we present a method for composing such surrogates to steer a pretrained model toward the distribution tilted by an unavailable $R^*$. Given a small feedback set of oracle rankings or numerical rewards, we introduce Mixing And Reward Tilting for INference-time Improvement (MARTINI), which learns a surrogate composition for plug-and-play use with standard inference-time steering methods. Our theory characterizes surrogate information limits and relates population recovery error to ideal-target KL at small tilt strength. For preferences, the bound additionally accounts for an irreducible mismatch between the Plackett-Luce population target and the conditional mean. Experiments demonstrate improved oracle-tilt fidelity in language generation and ImageNet alignment, and improved joint pose accuracy and validity in protein-ligand cofolding, without inference-time oracle queries.
Latent languages improve protein generation with transformers
Learning Latent Protein Languages for Autoregressive Generation
Abstract: Autoregressive transformers remain comparatively weak for protein sequence and structure generation. We study the role of target representation: amino acid tokens encode residue identities without explicit contextual semantics, while backbone coordinates require a discrete representation in our framework. We introduce two learned latent protein languages. Protein Latent Language (PLL) maps sequences to a 4,096-state contextual alphabet built on a frozen ESM-2 encoder, with one token per residue. Structure Latent Language (SLL) adapts GCP-VQVAE Lite with auxiliary sequence and confidence supervision while retaining decoding to backbone coordinates. We separately pretrain autoregressive transformer models on PLL and SLL tokens using next-token prediction, yielding PLLM and SLLM. Under matched downstream sequence training, PLLM has a fitted compute-scaling exponent of 0.038 versus 0.020 for the amino acid autoregressive model. In unconditional sequence generation, PLLM reduces the fraction of samples below a heuristic 1.5-bit residue-composition entropy threshold by 54% relative to the amino acid model across sampling temperatures. For sequence-to-structure prediction, replacing the original GCP-VQVAE Lite tokenizer with SLL reduces best validation perplexity by 34% under matched training. For long proteins, latent-token sampling is approximately 1,000 times faster than MSA-based AlphaFold2 in our measurements. In backbone generation, SLLM compares favorably with other generative models on diversity and novelty. We also observe early signs that using SLLM's internal token confidence for inference-time sampling can improve sequence-to-structure prediction quality beyond a single decoded sample. These results position learned latent protein languages as a promising substrate for autoregressive transformer scaling and inference-time sampling in protein generation.