Research Project
10387885
Abstract The overarching goal in this proposal is to understand how molecular motions and biophysical properties modulate protein interactions to promote normal homeostasis or pathological disease states. We investigate the relationship between protein dynamics and interactions in three contexts: 1) protein?fibrillar collagen interactions involved in platelet aggregation; 2) ?-synuclein (?S), an intrinsically disordered protein (IDP) whose misfolding and aggregation into amyloid fibrils and deposition into Lewy bodies are associated with debilitating synucleinopathies, such as Parkinson's Disease; and 3) the spike glycoprotein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), whose interaction with angiotensin converting enzyme 2 (ACE2) via the receptor binding domain (RBD) is the initial point of host cell entry. We have recently discovered that in each of these cases, conformational dynamics profoundly impact their atomic-to-nano scale properties and may affect their potential for biomolecular interactions. Despite the biological importance of these systems and the implications for their interactions on disease, the molecular determinants of these protein?protein interactions remain unanswered. Thus, we use a multifaceted approach integrating solution and solid-state NMR with biophysical, biological, and computational methods to address how molecular motions modulate protein interactions to promote normal homeostasis or pathological disease states. Gaining a molecular understanding of protein?protein interactions with each of these dynamic systems relies on state- of-the-art solution NMR instrumentation to be able to accurately measure timescales and fluctuations of these interaction events and to detect transient, lowly populated complexes.
