A weighted string kernel for protein fold recognition.

BACKGROUND: Alignment-free methods for comparing protein sequences have proved to be viable alternatives to approaches that first rely on an alignment of the sequences to be compared. Much work however need to be done before those methods provide reliable fold recognition for proteins whose sequences share little similarity. We have recently proposed an alignment-free method based on the concept of string kernels, SeqKernel (Nojoomi and Koehl, BMC Bioinformatics, 2017, 18:137). In this previous study, we have shown that while Seqkernel performs better than standard alignment-based methods, its applications are potentially limited, because of biases due mostly to sequence length effects. METHODS: In this study, we propose improvements to SeqKernel that follows two directions. First, we developed a weighted version of the kernel, WSeqKernel. Second, we expand the concept of string kernels into a novel framework for deriving information on amino acids from protein sequences. RESULTS: Using a dataset that only contains remote homologs, we have shown that WSeqKernel performs remarkably well in fold recognition experiments. We have shown that with the appropriate weighting scheme, we can remove the length effects on the kernel values. WSeqKernel, just like any alignment-based sequence comparison method, depends on a substitution matrix. We have shown that this matrix can be optimized so that sequence similarity scores correlate well with structure similarity scores. Starting from no information on amino acid similarity, we have shown that we can derive a scoring matrix that echoes the physico-chemical properties of amino acids. CONCLUSION: We have made progress in characterizing and parametrizing string kernels as alignment-based methods for comparing protein sequences, and we have shown that they provide a framework for extracting sequence information from structure.