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oai:figshare.com:article/34025306 2026-09-29T17:08:06Z category_1 category_4 category_146 category_915 category_7 category_8 category_12 category_14 category_19 category_132 category_133 category_135 portal_63 item_type_6 month_year_09_2026

A Directed TM→JM Coupling in Receptor Tyrosine Kinase Dimers, Set by Activating Mutations and the Membrane Environment Takeshi Sato (193052) Hiroko Tamagaki-Asahina (25138076) Biophysics Biochemistry Space Science Physical Sciences not elsewhere classified Medicine Microbiology Cell Biology Molecular Biology Pharmacology Infectious Diseases Plant Biology Computational Biology transmembrane – juxtamembrane tm → jm tm – jm mass fraction f hierarchical bayesian model bayesian network framework activating mutation raises measured activity state directivity thus tracks dependent rtk dimers dependent ordered wild type egfr leans ordered wild activating mutations ordered bilayers synthetic data structure alone rotational irreversibility posterior probabilities plane estimation plane circulation molecular dynamics membrane protein membrane environment experimental measurement domain drives distinguishing signaling cascade ); 93 ), 45 ); 1 ns The direction of conformational coupling in a membrane protein, that is, which domain drives which, has been inaccessible to experimental measurement. We recover this directivity from molecular dynamics (MD) of transmembrane–juxtamembrane (TM–JM) dimers of receptor tyrosine kinases EGFR and FGFR3. Coupling is detected with a Bayesian network framework (CASCADE); its direction is measured with PERI (Phase-plane Estimation of Rotational Irreversibility) as the net phase-plane circulation, validated on synthetic data, and resolved at 0.1 ns. Direction is summarized as the TM→JM directed-mass fraction f+ (0.5 = balanced) via a hierarchical Bayesian model. The activating TM mutants EGFR L658Q and FGFR3 A391E are TM→JM (posterior probabilities: 0.95 and 0.99); fluid wild-type EGFR leans the same way (0.93), in agreement with its experimentally reported constitutive activity in fluid but not ordered bilayers; the ligand-dependent ordered wild-type is balanced (0.45); and an activating mutation raises the TM→JM bias above the ordered wild-type with probability 0.94. The directivity thus tracks the measured activity state of the receptor, distinguishing signaling-competent from ligand-dependent RTK dimers by a property not apparent from structure alone. 2026-09-29T00:00:00Z Text Journal contribution 10.1021/jacs.6c10487.s001 https://figshare.com/articles/journal_contribution/A_Directed_TM_JM_Coupling_in_Receptor_Tyrosine_Kinase_Dimers_Set_by_Activating_Mutations_and_the_Membrane_Environment/34025306 CC BY-NC 4.0