Modularity of Protein Folds as a Tool for Template-Free Modeling of Structures

Predicting the three-dimensional structure of proteins from their amino acid sequences remains a challenging problem in molecular biology. While the current structural coverage of proteins is almost exclusively provided by template-based techniques, the modeling of the rest of the protein sequences increasingly require template-free methods. However, template-free modeling methods are much less reliable and are usually applicable for smaller proteins, leaving much space for improvement. We present here a novel computational method that uses a library of supersecondary structure fragments, known as Smotifs, to model protein structures. The library of Smotifs has saturated over time, providing a theoretical foundation for efficient modeling. The method relies on weak sequence signals from remotely related protein structures to create a library of Smotif fragments specific to the target protein sequence. This Smotif library is exploited in a fragment assembly protocol to sample decoys, which are assessed by a composite scoring function. Since the Smotif fragments are larger in size compared to the ones used in other fragment-based methods, the proposed modeling algorithm, SmotifTF, can employ an exhaustive sampling during decoy assembly. SmotifTF successfully predicts the overall fold of the target proteins in about 50% of the test cases and performs competitively when compared to other state of the art prediction methods, especially when sequence signal to remote homologs is diminishing. Smotif-based modeling is complementary to current prediction methods and provides a promising direction in addressing the structure prediction problem, especially when targeting larger proteins for modeling.Author Summary: Each protein folds into a unique three-dimensional structure that enables it to carry out its biological function. Knowledge of the atomic details of protein structures is therefore a key to understanding their function. Advances in high throughput experimental technologies have lead to an exponential increase in the availability of known protein sequences. Although strong progress has been made in experimental protein structure determination, it remains a fact that more than 99% of structural information is provided by computational modeling methods. We describe here a novel structure prediction method, SmotifTF, which uses a unique library of known protein fragments to assemble the three-dimensional structure of a sequence. The fragment library has saturated over time and therefore provides a complete set of building blocks required for model building. The method performs competitively compared to existing methods of structure prediction.