Sequence activity modeling

The term Quantitative Sequence-Activity Models (QSAMs) is used instead of quantitative structure-activity relationships when referred to the research on relationships between structure and activities of molecules of biological interest [Jonsson, Norberg et al., 1993]. 

Jonsson, J., Norberg, T. and Carlsson, L. (1993) Quantitative sequence-activity models (QSAM) -... 

This paper describes the application of sequence-activity modeling techniques to identify amino acid residues within one protein (proteinase K) that contribute to specific functions. We show that combining amino acids identified as beneficial by mathematical modeling results in a protein with improved activity. We also show that different amino acids are important for different functions, underscoring the importance of using a screen that accurately reflects the commercially desired protein function. 

The utility of a sequence-activity model lies in its ability to predict the activity of variants that have not been measured, or to identify amino acid variations that contribute positively to a specific protein property and that can then be experimentally combined. To test our sequence activity model for heat-tolerant hydrolyzers of AAPL-p-NA, we analyzed the regression coefficients from the model, as shown in Figure 4. 

Figure 4. Regression coefficients (squares, left axis) of variant amino acids derived from the PLSR sequence-activity model Number of occurrences (diamonds, right axis) are also shown. Changes from the wild type sequence are circled.

We have described a method for engineering proteins based on design, synthesis and testing of small numbers of iiulividual variants followed by mathematical modeling to determine a sequence-activity relationship. We have also shown that sequence-activity models can be used predictively to design improved variants. 

Together these results suggest a two-step activation model in which ligand first binds to the high affinity sequence on the receptor N-terminus thereby tethering it to the receptor. Subsequently, in an intramolecular docking event, the tethered ligand docks to a secondary site on the... 

Knowing the causes of the changes in stability and activity sequences in model systems and in enzymes and knowing the sequences of activity which appear in biological systems, we can draw tentative conclusions which are open to test by the above probe studies. 

Modeling the Proteinase K Sequence Activity Relationship for Heat Tolerance... 

For each of the proteinase K activities tested, we used partial least squares regression (PLSR) to model the relationship between amino acid variation and the variations in proteinase activities (the sequence-activity relationship). The application of these methods to nucleic acids, peptides and proteins has been described previously (7, II, 12, 28-30)... 

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