Primary and secondary dimer interfaces of the fibroblast growth factor receptor 3 transmembrane domain: characterization via multiscale molecular dynamics simulations.

[achondroplasia]

Receptor tyrosine kinases are single -pass membrane proteins that form dimers within the membrane . The interactions of their transmembrane domains (TMDs ) play a key role in dimerization and signaling . Fibroblast growth factor receptor 3 (FGFR 3 ) is of interest as a G 380 R mutation in its TMD is the underlying cause of ~99 % of the cases of achondroplasia , the most common form of human dwarfism . The structural consequences of this mutation remain uncertain : the mutation shifts the position of the TMD relative to the lipid bilayer but does not alter the association free energy . We have combined coarse -grained and all-atom molecular dynamics simulations to study the dimerization of wild-type , heterodimer , and mutant FGFR 3 TMDs . The simulations reveal that the helices pack together in the dimer to form a flexible interface . The primary packing mode is mediated by a Gx 3 G motif . There is also a secondary dimer interface that is more highly populated in heterodimer and mutant configurations that may feature in the molecular mechanism of pathology . Both coarse -grained and atomistic simulations reveal a significant shift of the G 380 R mutant dimer TMD relative to the bilayer to allow interactions of the arginine side chain with lipid headgroup phosphates .