# Towards A Generative Protein Evolution Machine with DPLM-Evo

arXiv: https://arxiv.org/abs/2605.00182 · HTML: https://mlsanity.com/paper/2605.00182/

## Key facts

- Cited by 3 papers in the map (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 37 of its 60 references that are in the map.
- First posted on arXiv 30 Apr 2026.

## Placed in

- Diffusion models / [Flow matching, time series and science](https://mlsanity.com/diffusion/flow-matching-time-series-and-science/)

## Builds on (most cited first, 30 of 37)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Denoising Diffusion Implicit Models](https://mlsanity.com/paper/2010.02502/) (2020)
- [Score-Based Generative Modeling through Stochastic Differential Equations](https://mlsanity.com/paper/2011.13456/) (2020)
- [Deep Unsupervised Learning using Nonequilibrium Thermodynamics](https://mlsanity.com/paper/1503.03585/) (2015)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [Large Language Diffusion Models](https://mlsanity.com/paper/2502.09992/) (2025)
- [Simple and Effective Masked Diffusion Language Models](https://mlsanity.com/paper/2406.07524/) (2024)
- [Simplified and Generalized Masked Diffusion for Discrete Data](https://mlsanity.com/paper/2406.04329/) (2024)
- [Argmax Flows and Multinomial Diffusion: Learning Categorical Distributions](https://mlsanity.com/paper/2102.05379/) (2021)
- [Dream 7B: Diffusion Large Language Models](https://mlsanity.com/paper/2508.15487/) (2025)
- [Your Absorbing Discrete Diffusion Secretly Models the Conditional Distributions of Clean Data](https://mlsanity.com/paper/2406.03736/) (2024)
- [Scaling Diffusion Language Models via Adaptation from Autoregressive Models](https://mlsanity.com/paper/2410.17891/) (2024)
- [Evaluating Protein Transfer Learning with TAPE](https://mlsanity.com/paper/1906.08230/) (2019)
- [DiffusionBERT: Improving Generative Masked Language Models with Diffusion Models](https://mlsanity.com/paper/2211.15029/) (2022)
- [Levenshtein Transformer](https://mlsanity.com/paper/1905.11006/) (2019)
- [Scaling up Masked Diffusion Models on Text](https://mlsanity.com/paper/2410.18514/) (2024)
- [ProGen2: Exploring the Boundaries of Protein Language Models](https://mlsanity.com/paper/2206.13517/) (2022)
- [Protein Design with Guided Discrete Diffusion](https://mlsanity.com/paper/2305.20009/) (2023)
- [Simple Guidance Mechanisms for Discrete Diffusion Models](https://mlsanity.com/paper/2412.10193/) (2024)
- [A Reparameterized Discrete Diffusion Model for Text Generation](https://mlsanity.com/paper/2302.05737/) (2023)
- [The Diffusion Duality](https://mlsanity.com/paper/2506.10892/) (2025)
- [Fully Non-autoregressive Neural Machine Translation: Tricks of the Trade](https://mlsanity.com/paper/2012.15833/) (2020)
- [Diffusion Language Models Are Versatile Protein Learners](https://mlsanity.com/paper/2402.18567/) (2024)
- [Generalized Interpolating Discrete Diffusion](https://mlsanity.com/paper/2503.04482/) (2025)
- [Structure-informed Language Models Are Protein Designers](https://mlsanity.com/paper/2302.01649/) (2023)
- [DPLM-2: A Multimodal Diffusion Protein Language Model](https://mlsanity.com/paper/2410.13782/) (2024)
- [Edit Flows: Flow Matching with Edit Operations](https://mlsanity.com/paper/2506.09018/) (2025)
- [DINOISER: Diffused Conditional Sequence Learning by Manipulating Noises](https://mlsanity.com/paper/2302.10025/) (2023)
- [Diffusion Language Models Can Perform Many Tasks with Scaling and Instruction-Finetuning](https://mlsanity.com/paper/2308.12219/) (2023)
- [NAT: Neural Architecture Transformer for Accurate and Compact Architectures](https://mlsanity.com/paper/1910.14488/) (2019)

## Built on by (most cited first, 3 of 3)

- [AMix-2: Establishing Protein as a Native Modality in Large Language Models](https://mlsanity.com/paper/2605.30963/) (2026)
- [PFArena: Benchmarking Language Models for Protein Modification](https://mlsanity.com/paper/2609.28921/) (2026)
- [Linear Fitness Subspace in Protein Language Models Enables Sample-Efficient Directed Evolution](https://mlsanity.com/paper/2610.07607/) (2026)

## Abstract (arXiv)

Proteins are shaped by gradual evolution under biophysical and functional constraints. Protein language models learn rich evolutionary constraints from large-scale sequences, and discrete diffusion-based protein language models~(eg, DPLMs) are promising for both understanding and generation. However, existing DPLMs typically rely on masked diffusion that contradicts a simple biological intuition: proteins evolve through accumulated edits, not by emerging from masks. Consequently, these frameworks lack explicit pretraining objectives for substitution and insertion/deletion (indel) operations, limiting both optimization-style post-editing and flexible guided generation. To address these limitations, we present DPLM-Evo, an evolutionary discrete diffusion framework that explicitly predicts substitution, insertion, and deletion operations during denoising. DPLM-Evo decouples an upsampled-length latent alignment space from the variable-length observed sequence space, which makes indel-aware generation tractable. To better align substitutions with real evolution, we further introduce a contextualized evolutionary noising kernel that produces biologically informed, context-dependent mutation patterns. Across tasks, DPLM-Evo improves sequence understanding and achieves state-of-the-art mutation effect prediction performance on ProteinGym in the single-sequence setting. It also enables variable-length simulated evolution, and post-editing/optimization of existing proteins via explicit edit trajectories.