Cracking the Capsid Code: A Computationally-Feasible Approach for Investigating Virus-Excipient Interactions in Biologics Design

The efficacy and equitable distribution of viral biologics---including vaccines and virus-like particles---is hindered due to their inherently low shelf life. To increase the longevity of such products, formulations are usually developed with small molecule additives known as excipients. Incorporating excipients is a costly and time-consuming process due to the large excipient design space and unknown mechanisms underlying excipient-virus interactions. Molecular dynamics simulations are, in theory, well-equipped to efficiently investigate these mechanisms. However, the massive size of fully assembled viral capsids---the protein shell that encapsulates the viral genome---demands computational resources well beyond the requirements of conventional simulations. There exists a need for a novel method that enables high-throughput investigations of virus-excipient interactions at the molecular level. Here, we introduce CapSACIN --- a computational framework for Cap sid S urface A bstraction and C omputationally- I nduced N anofragmentation. We demonstrate the applicability of this workflow to a model non-enveloped virus, porcine parvovirus (PPV). Through simulations of PPV surface models, we observe that the 2-fold axis of symmetry is significantly weaker at a molecular level than the 3- or 5-fold axes of symmetry. Further, we present results demonstrating excellent agreement with experimentally-determined excipient effects on PPV thermal stability.