Protein is the term proposed by the Swedish chemist Jacob Berzelius to compounds containing nitrogen and constituted by a combination of amino acids linked by a bond, called peptide bond ( Fruton, 1985 Wisniak, 2000 Lehninger et al., 2005 Voet et al., 2014). In this mini-review, we provide an overview of the breakthroughs in protein structure prediction before and after AlphaFold2 emergence.

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. 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. Despite its current impact in the field, AlphaFold2 has limitations. 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. In this context, studies have emerged to predict protein structures by methods based on a template or free modeling. 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. 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. Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of São Paulo Medical School, São Paulo, Brazil.

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