# TriFit: Trimodal Fusion with Protein Dynamics for Mutation Fitness Prediction

arXiv: https://arxiv.org/abs/2604.12026 · HTML: https://mlsanity.com/paper/2604.12026/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Medical and biomedical MoE, one of 12 directions in Mixture-of-experts.
- Builds on 3 of its 22 references that are in the map.
- First posted on arXiv 13 Apr 2026.

## Placed in

- Mixture-of-experts / [Medical and biomedical MoE](https://mlsanity.com/moe/medical-and-biomedical-moe/)

## Builds on (most cited first, 3 of 3)

- [Representation Learning with Contrastive Predictive Coding](https://mlsanity.com/paper/1807.03748/) (2018)
- [SGDR: Stochastic Gradient Descent with Warm Restarts](https://mlsanity.com/paper/1608.03983/) (2016)
- [Learning from Protein Structure with Geometric Vector Perceptrons](https://mlsanity.com/paper/2009.01411/) (2020)

## Abstract (arXiv)

Predicting the functional impact of single amino acid substitutions (SAVs) is central to understanding genetic disease and engineering therapeutic proteins. While protein language models and structure-based methods have achieved strong performance on this task, they systematically neglect protein dynamics; residue flexibility, correlated motions, and allosteric coupling are well-established determinants of mutational tolerance in structural biology, yet have not been incorporated into supervised variant effect predictors. We present TriFit, a multimodal framework that integrates sequence, structure, and protein dynamics through a four-expert Mixture-of-Experts (MoE) fusion module with trimodal cross-modal contrastive learning. Sequence embeddings are extracted via masked marginal scoring with ESM-2 (650M); structural embeddings from AlphaFold2-predicted C-alpha geometries; and dynamics embeddings from Gaussian Network Model (GNM) B-factors, mode shapes, and residue-residue cross-correlations. The MoE router adaptively weights modality combinations conditioned on the input, enabling protein-specific fusion without fixed modality assumptions. On the ProteinGym substitution benchmark (217 DMS assays, 696k SAVs), TriFit achieves AUROC 0.897 +/- 0.0002, outperforming all supervised baselines including Kermut (0.864) and ProteinNPT (0.844), and the best zero-shot model ESM3 (0.769). Ablation studies confirm that dynamics provides the largest marginal contribution over pairwise modality combinations, and TriFit achieves well-calibrated probabilistic outputs (ECE = 0.044) without post-hoc correction.