Unsupervised modeling of mutational landscapes of adeno-associated viruses viability

ABSTRACT Adeno-associated viruses 2 (AAV2) are minute viruses renowned for their capacity to infect human cells and akin organisms. They have recently emerged as prominent candidates in the field of gene therapy, primarily attributed to their inherent non-pathogenic nature in humans and the safety associated with their manipulation. The efficacy of AAV2 as gene therapy vectors hinges on their ability to infiltrate host cells and subsequently replicate within them, a phenomenon reliant on their competence to construct a capsid capable of breaching the nucleus of the target cell. To enhance their infection potential, researchers have extensively scrutinized various combinatorial libraries by introducing mutations into the capsid, aiming to boost their effectiveness. The emergence of high-throughput experimental techniques, like Deep Mutational Scanning (DMS), has made it feasible to experimentally assess the fitness of these libraries for their intended purpose. Notably, machine learning is starting to demonstrate its potential in addressing predictions within the mutational landscape from sequence data. In this context, we introduce a biophysically-inspired model designed to predict the viability of genetic variants in DMS experiments. This model is tailored to a specific segment of the CAP region within AAV2’s capsid protein. To evaluate its effectiveness, we conduct model training with diverse datasets, each tailored to explore different aspects of the mutational landscape influenced by the selection process. Our assessment of the biophysical model centers on two primary objectives: (i) providing quantitative forecasts for the log-selectivity of variants and (ii) deploying it as a binary classifier to categorize sequences into viable and non-viable classes.