BPS2026 – Lipid asymmetry and signaling activation of receptor tyrosine kinases

Receptor tyrosine kinases (RTKs) are transmembrane proteins central to signaling pathways that regulate proliferation, differentiation, migration, and metabolism. Despite structural diversity, they share a conserved architecture comprising an extracellular ligand-binding domain, a single-pass transmembrane helix (TMD), a cytoplasmic juxtamembrane domain (JMD), and kinase domain (KD). Many RTKs are promiscuous in ligand binding, and the precise mechanisms of signal transduction in the TMD remain unresolved, lacking a broadly applicable consensus model. While prior studies have dissected individual domains, kinetics, and dimer structures, a unified understanding of conformational changes and the role of lipid compositions is still absent. Here, we apply multi-scale molecular dynamics and free-energy calculations to investigate the TMD helices and JMDs of two RTKs, FGFR3, and TrkA, in biologically relevant membrane environments. We first characterize the stability of NMR-resolved structures, capture spontaneous helix dimerization, and probe how cancer-associated membrane physiology promotes signaling. We then employ weighted ensemble method to capture dynamics on long timescales more accurately capturing slow-mode behavior. Our results identify multiple stable dimer conformations, reveal how disease-linked mutations alter dimerization angles and protein-membrane interfaces, and quantify the free-energy costs of these mutations. Constructing energy landscapes from these simulations, we highlight how transmembrane mutations and lipid asymmetry influence dimerization. Together, our findings establish a physical framework for understanding RTK transmembrane helix dynamics. By integrating mutation effects with membrane composition, this work advances mechanistic models of RTK activation and provides a foundation for future experimental validation.