Unlocking Multimodal Protein Language Models at Inference Time

Inference-time methods that aggregate and prune multiple samples have emerged as a powerful paradigm for steering large language models, yet we lack any principled understanding of their accuracy-cost tradeoffs. In this paper, we introduce a route to rigorously study such approaches using the lens of particle filtering algorithms such as Sequential Monte Carlo (SMC). Given a base language model and a process reward model estimating expected terminal rewards, we ask: how accurately can we sample from a target distribution given some number of process reward evaluations? Theoretically, we identify (1) simple criteria enabling non-asymptotic guarantees for SMC; (2) algorithmic improvements to SMC; and (3) a fundamental limit faced by all particle filtering methods. Empirically, we demonstrate that our theoretical criteria effectively govern the sampling error of SMC, though not necessarily its final accuracy, suggesting that theoretical perspectives beyond sampling may be necessary.

A plethora of protein language models have been released in recent years. Yet comparatively little work has addressed how to best sample from them to optimize desired biological properties. We fill this gap by proposing a flexible, effective sampling method for masked language models (MLMs), and by systematically evaluating models and methods both in silico and in vitro on actual antibody therapeutics campaigns. Firstly, we propose sampling with stochastic beam search, exploiting the fact that MLMs are remarkably efficient at evaluating the pseudo-perplexity of the entire 1-edit neighborhood of a sequence. Reframing generation in terms of entire-sequence evaluation enables flexible guidance with multiple optimization objectives. Secondly, we report results from our extensive in vitro head-to-head evaluation for the antibody engineering setting. This reveals that the choice of sampling method can have a substantial impact, motivating future research into this under-explored area.

Modern Protein Language Models (PLMs) apply transformer-based model architectures from natural language processing to biological sequences, predicting a variety of protein functions and properties. However, protein language has key differences from natural language, such as a rich functional space despite a vocabulary of only 20 amino acids. These differences motivate research into how transformer-based architectures operate differently in the protein domain and how we can better leverage PLMs to solve protein-related tasks. In this work, we begin by directly comparing how the distribution of information stored across layers of attention heads differs between the protein and natural language domain. Furthermore, we adapt a simple early-exit technique-originally used in the natural language domain to improve efficiency at the cost of performance-to achieve both increased accuracy and substantial efficiency gains in protein non-structural property prediction by allowing the model to automatically select protein representations from the intermediate layers of the PLMs for the specific task and protein at hand. We achieve performance gains ranging from 0.4 to 7.01 percentage points while simultaneously improving efficiency by over 10 percent across models and non-structural prediction tasks. Our work opens up an area of research directly comparing how language models change behavior when moved into the protein domain and advances language modeling in biological domains.