Many membrane receptors form quaternary contacts, which help stabilize oligomeric structures, and tuned interfacial conformations have recently been shown to have significant influence on downstream signaling (1). Modulating the conformational dynamics of membrane signaling complexes has vast potential to generate useful therapeutic and synthetic biology functions. However, such precise engineering requires a deep understanding of the forces that stabilize membrane protein complexes. Certain membrane protein oligomers exhibit unexpectedly high kinetic stability (2), but the structural origins are unclear. We seek to dissect the molecular determinants of oligomeric kinetic stability by computationally designing dynamic membrane protein assemblies with tunable energetics that can be socketed into signaling complexes as interface motifs for cellular engineering.

Over 40% of human signaling is governed by peptide ligands, many of which bind to and activate GPCRs. One of the challenges of understanding peptide receptor signaling is to deorphanize receptors and discover which endogenous ligands trigger signal transduction. Peptides are highly dynamic and conformationally diverse, making the prediction of their complexed structure with membrane receptors challenging. However, recent advances in machine-learning, homology modeling, and rational design of receptor:peptide complexes have created opportunities to uncover the activation properties of orphan peptide-activated receptors (3). Through hybrid computational and experimental methods we aim to define the molecular determinants of peptide binding that trigger activation in order to demystify this elusive class of receptors.

Many effector proteins downstream of membrane receptors serve as scaffolds that organize localization and activity of signaling pathways. We are interested in modeling and designing dynamic scaffold complexes to control cellular signaling from an intracellular angle.