One of the most promising approaches to improving the stability of biologics is chemical conjugation with polymers, particularly poly(ethylene glycol) (PEG), to form protein-polymer conjugates. While PEGylation has been shown to improve pharmacokinetic properties and prolong therapeutic efficacy of biologics, its effects on protein stability and activity have been unpredictable, with studies reporting both an improvement and reduction in stability. Further, much of the knowledge surrounding PEGylation's effects remains empirical rather than mechanistically understood. These challenges underscore the need for predictive models that elucidate the molecular mechanisms governing PEGylation-driven protein stabilization.