Fig. 1

Workflow of FALCON2 prediction server. The prediction procedure of FALCON2 mainly consists of the following four steps: (i) Constructing MSA for target protein: For a target protein input by user, FALCON2 first searches its homologous proteins within a variety of sequence databases including Uniclust, Uniref, Metaclust, BFD and MGnify. The identified homologous proteins are organized as a multiple sequence alignment (MSA). (ii) Predicting candidate structures using ProALIGN: For each target protein, FALCON2 predicts its candidate structures by running ProALIGN and ProFOLD simultaneously. Specifically, ProALIGN takes the constructed MSA as input and calculates target-template alignment with all templates in a pre-defined library. The library will be regularly updated. ProALIGN selects the most likely target-template alignment according to contact information, and subsequently builds candidate structures with reference to the selected templates. (iii) Predicting candidate structures using ProFOLD: ProFOLD uses an end-to-end framework, called CopulaNet, to estimate inter-residue distances directly from MSA of target protein. ProFOLD transforms the estimated inter-residue distances into an energy potential, and applies the gradient-descent technique to build candidate structures that minimize this potential function. (iv) Selecting the best candidate structure: For all the candidate structures predicted by ProALIGN and ProFOLD, FALCON2 evaluates their quality through running ProQ3D, a software for structure quality assessment. The candidate structure with the highest quality will be reported as the final prediction result by FALCON2