Synthesis Cost-Optimal Targeted Mutant Protein Libraries

Protein variant libraries produced by site-directed mutagenesis are a useful tool utilized by protein engineers to explore variants with potentially improved properties, such as activity and stability. These libraries are commonly built by selecting residue positions and alternative beneficial mutations for each position. All possible combinations are then constructed and screened, by incorporating degenerate codons at mutation sites. These degenerate codons often encode additional unwanted amino acids or even STOP codons. Our study aims to take advantage of annealing based recombination of oligonucleotides during synthesis and utilize multiple degenerate codons per mutation site to produce targeted protein libraries devoid of unwanted variants. Toward this goal we created an algorithm to calculate the minimum number of degenerate codons necessary to specify any given amino acid set, and a dynamic programming method that uses this algorithm to optimally partition a DNA target sequence with degeneracies into overlapping oligonucleotides, such that the total cost of synthesis of the target mutant protein library is minimized. Computational experiments show that, for a modest increase in DNA synthesis costs, beneficial variant yields in produced mutant libraries are increased by orders of magnitude, an effect particularly pronounced in large combinatorial libraries

Prompting for Discovery: Flexible Sense-Making for AI Art-Making with Dreamsheets

Design space exploration (DSE) for Text-to-Image (TTI) models entails navigating a vast, opaque space of possible image outputs, through a commensurately vast input space of hyperparameters and prompt text. Minor adjustments to prompt input can surface unexpectedly disparate images. How can interfaces support end-users in reliably steering prompt-space explorations towards interesting results? Our design probe, DreamSheets, supports exploration strategies with LLM-based functions for assisted prompt construction and simultaneous display of generated results, hosted in a spreadsheet interface. The flexible layout and novel generative functions enable experimentation with user-defined workflows. Two studies, a preliminary lab study and a longitudinal study with five expert artists, revealed a set of strategies participants use to tackle the challenges of TTI design space exploration, and the interface features required to support them - like using text-generation to define local "axes" of exploration. We distill these insights into a UI mockup to guide future interfaces.Comment: 13 pages, 14 figures, currently under revie