Machine learning based predictive model for the analysis of sequence activity relationships using protein spectra and protein descriptors

Accurately establishing the connection between a protein sequence and its function remains a focal point within the field of protein engineering, especially in the context of predicting the effects of mutations. From this, there has been a continued drive to build accurate and reliable predictive models via machine learning that allow for the virtual screening of many protein mutant sequences, measuring the relationship between sequence and ‘fitness’ or ‘activity’, commonly known as a Sequence-Activity-Relationship (SAR). An important preliminary stage in the building of these predictive models is the encoding of the chosen sequences. Evaluated in this work is a plethora of encoding strategies using the Amino Acid Index database, where the indices are transformed into their spectral form via Digital Signal Processing (DSP) techniques, as well as numerous protein structural and physiochemical descriptors. The encoding strategies are explored on a dataset curated to measure the thermostability of various mutants from a recombination library, designed from parental cytochrome P450s. In this work it was concluded that the implementation of protein spectra in concatenation with protein descriptors, together with the Partial Least Squares Regression (PLS) algorithm, gave the most noteworthy increase in the quality of the predictive models (as described in Encoding Strategy C), highlighting their utility in identifying an SAR. The accompanying software produced for this paper is termed pySAR (Python Sequence-Activity-Relationship), which allows for a user to find the optimal arrangement of structural and or physiochemical properties to encode their specific mutant library dataset; the source code is available at: https://github.com/amckenna41/pySAR.