Neural network-based prediction of mutation-induced protein stability changes in Staphylococcal nuclease at 20...

Protein-based therapeutics are playing an increasingly important role in the treatment of diseases, including diabetes and cancer. The viability of these treatments, however, are highly dependent on the stability of the therapeutic, since stability affects both the shelf life of the therapeutic as well as its active life in the body. Stability engineering can, therefore, be used to increase the effectiveness of protein-based therapeutics. Computational methods of protein stability prediction have been under development for about a decade, but complex molecular interactions make stability prediction difficult and computationally intensive. A rapid computational method of protein stability prediction is developed using feed-forward neural networks and used to predict mutation-induced stability changes in Staphylococcal nuclease. The input to the neural network consisted of sequences of evolutionarily based amino acid similarity scores that were obtained through the comparison of the amino acids in a mutation containing sequence to their positional counterparts in the baseline wild-type amino acid sequence. A training set was created which consisted of similarity score sequences, for which the stabilities of the corresponding amino acid sequences were known, paired with the relative stabilities of the sequences to that of the baseline. Back-propagation of error was used to train the network to output accurate relative stability scores for the sequences in the training set. Neural network-based relative stability predictions for 55 sequences containing mutation combinations not found in the training set had an accuracy of 92.8%.