# Multi-level Protein Representation Learning for Blind Mutational Effect Prediction

arXiv: https://arxiv.org/abs/2306.04899 · HTML: https://mlsanity.com/paper/2306.04899/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Builds on 19 of its 53 references that are in the map.
- First posted on arXiv 8 Jun 2023.

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

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [BERT: Pre-training of Deep Bidirectional Transformers for Language Understanding](https://mlsanity.com/paper/1810.04805/) (2018)
- [Adam: A Method for Stochastic Optimization](https://mlsanity.com/paper/1412.6980/) (2014)
- [Semi-Supervised Classification with Graph Convolutional Networks](https://mlsanity.com/paper/1609.02907/) (2016)
- [Graph Attention Networks](https://mlsanity.com/paper/1710.10903/) (2017)
- [Megatron-LM: Training Multi-Billion Parameter Language Models Using Model Parallelism](https://mlsanity.com/paper/1909.08053/) (2019)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [Learning from Protein Structure with Geometric Vector Perceptrons](https://mlsanity.com/paper/2009.01411/) (2020)
- [ProtTrans: Towards Cracking the Language of Life's Code Through Self-Supervised Deep Learning and High Performance Computing](https://mlsanity.com/paper/2007.06225/) (2020)
- [Protein Representation Learning by Geometric Structure Pretraining](https://mlsanity.com/paper/2203.06125/) (2022)
- [ProGen2: Exploring the Boundaries of Protein Language Models](https://mlsanity.com/paper/2206.13517/) (2022)
- [Iterative Refinement Graph Neural Network for Antibody Sequence-Structure Co-design](https://mlsanity.com/paper/2110.04624/) (2021)
- [BERTology Meets Biology: Interpreting Attention in Protein Language Models](https://mlsanity.com/paper/2006.15222/) (2020)
- [Tranception: protein fitness prediction with autoregressive transformers and inference-time retrieval](https://mlsanity.com/paper/2205.13760/) (2022)
- [Conditional Antibody Design as 3D Equivariant Graph Translation](https://mlsanity.com/paper/2208.06073/) (2022)
- [OntoProtein: Protein Pretraining With Gene Ontology Embedding](https://mlsanity.com/paper/2201.11147/) (2022)
- [RITA: a Study on Scaling Up Generative Protein Sequence Models](https://mlsanity.com/paper/2205.05789/) (2022)
- [Improved Protein-ligand Binding Affinity Prediction with Structure-Based Deep Fusion Inference](https://mlsanity.com/paper/2005.07704/) (2020)
- [Accurate and Definite Mutational Effect Prediction with Lightweight Equivariant Graph Neural Networks](https://mlsanity.com/paper/2304.08299/) (2023)

## Built on by (most cited first, 1 of 1)

- [Graph Denoising Diffusion for Inverse Protein Folding](https://mlsanity.com/paper/2306.16819/) (2023)

## Abstract (arXiv)

Directed evolution plays an indispensable role in protein engineering that revises existing protein sequences to attain new or enhanced functions. Accurately predicting the effects of protein variants necessitates an in-depth understanding of protein structure and function. Although large self-supervised language models have demonstrated remarkable performance in zero-shot inference using only protein sequences, these models inherently do not interpret the spatial characteristics of protein structures, which are crucial for comprehending protein folding stability and internal molecular interactions. This paper introduces a novel pre-training framework that cascades sequential and geometric analyzers for protein primary and tertiary structures. It guides mutational directions toward desired traits by simulating natural selection on wild-type proteins and evaluates the effects of variants based on their fitness to perform the function. We assess the proposed approach using a public database and two new databases for a variety of variant effect prediction tasks, which encompass a diverse set of proteins and assays from different taxa. The prediction results achieve state-of-the-art performance over other zero-shot learning methods for both single-site mutations and deep mutations.