Electrical engineering

Homology modeling

Enzyme

Protein Data Bank (RCSB PDB)

Biology

Gene

Protein Data Bank

Engineering

Genome

Protein superfamily

Threading (protein sequence)

Protein folding

Protein structure prediction

Folding (DSP implementation)

Computer science

Protein structure

Computational biology

Genetics

Biochemistry

Cell Reports Methods

Structure prediction for proteins lacking homologous templates in the Protein Data Bank (PDB) remains a significant unsolved problem. We developed a protocol, C-I-TASSER, to integrate interresidue contact maps from deep neural-network learning with the cutting-edge I-TASSER fragment assembly simulations. Large-scale benchmark tests showed that C-I-TASSER can fold more than twice the number of non-homologous proteins than the I-TASSER, which does not use contacts. When applied to a folding experiment on 8,266 unsolved Pfam families, C-I-TASSER successfully folded 4,162 domain families, including 504 folds that are not found in the PDB. Furthermore, it created correct folds for 85% of proteins in the SARS-CoV-2 genome, despite the quick mutation rate of the virus and sparse sequence profiles. The results demonstrated the critical importance of coupling whole-genome and metagenome-based evolutionary information with optimal structure assembly simulations for solving the problem of non-homologous protein structure prediction.

Folding non-homologous proteins by coupling deep-learning contact maps with I-TASSER assembly simulations