Before and after AlphaFold2: An overview of protein structure prediction

Abstract

Three-dimensional protein structure is directly correlated with its function and its determination is critical to understanding biological processes and addressing human health and life science problems in general. Although new protein structures are experimentally obtained over time, there is still a large difference between the number of protein sequences placed in Uniprot and those with resolved tertiary structure. In this context, studies have emerged to predict protein structures by methods based on a template or free modeling. In the last years, different methods have been combined to overcome their individual limitations, until the emergence of AlphaFold2, which demonstrated that predicting protein structure with high accuracy at unprecedented scale is possible. Despite its current impact in the field, AlphaFold2 has limitations. Recently, new methods based on protein language models have promised to revolutionize the protein structural biology allowing the discovery of protein structure and function only from evolutionary patterns present on protein sequence. Even though these methods do not reach AlphaFold2 accuracy, they already covered some of its limitations, being able to predict with high accuracy more than 200 million proteins from metagenomic databases. In this mini-review, we provide an overview of the breakthroughs in protein structure prediction before and after AlphaFold2 emergence.

Keywords: AlphaFold; free modeling; protein language model; protein structure prediction; template-based modeling.

FIGURE 1

Timeline with main events and programs/webserver in the protein structure prediction. Colored boxes indicate the method or important event in the field.

FIGURE 2

The top 10 programs and/or web servers in CASP14 in (A) TBM-easy, (B) TBM-hard, (C) TBM/FM, and (D) FM categories considering summed z-score. Data extracted by CASP official website.