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.
Shastry et al. (2026) studied this question.