Protein expression screens are routinely used to identify biological processes deregulated upon disease development or upon specific cellular perturbations. Generating molecular hypotheses from these ‘omic data remains challenging, however, and many molecular events that modulate protein function do not involve altered protein levels. With this project, I propose a new paradigm. I propose that by measuring altered structures of proteins on a global scale, we can capture altered functional states of proteins and proteomes. I propose that the new approach will support the generation of testable molecular hypotheses from global data and the development of new frameworks for the modelling of biological systems. Building on a unique mass spectrometric approach my lab developed, which captures protein structural changes on a proteome-wide scale, we will assess the performance of the global structural readout at analyzing complex phenotypes. We will apply it to a biomedical problem of interest to my lab: the functional and pathological implications of protein aggregates or superassemblies (SAs). Protein aggregates form not only during disease but also under physiological conditions. These structures regulate important normal processes and contribute to cellular architecture. Using the new structural approach, we will identify and characterize networks of novel functional SAs in E. coli, mouse, and human proteomes. We will assess how genomic variation, environment and age modulate protein structures and SA assembly and how SAs are linked to phenotypes. Last, we will translate our approach to a clinical setting and ask whether altered protein structures can serve as biomarkers of disease, specifically Parkinson’s disease and how SAs underlie Parkinson’s subtypes. We will collect the wealth of dynamic structural data generated through this project into an Atlas of Structural Proteome Dynamics and use the data to shed new light on features of the structural proteome.