Effect of N‑Terminal Myristoylation on the Active Conformation of Gα i1–GTP

G proteins are part of the G-protein-coupled receptor (GPCR) signal transduction cascade in which they transfer a signal from the membrane-embedded GPCR to other proteins in the cell. In the case of the inhibitory G-protein heterotrimer, permanent N-terminal myristoylation can transiently localize the Gα i subunit at the membrane as well as crucially influence Gα i ’s function in the GTP-bound conformation. The attachment of lipids to proteins is known to be essential for membrane trafficking; however, our results suggest that lipidation is also important for protein–protein interactions during signal transduction. Here we investigate the effect of myristoylation on the structure and dynamics of soluble Gα i1 and its possible implication for signal transduction. A 2 μs classical molecular dynamics simulation of a myristoylated Gα i1–GTP complex suggests that the myristoyl-induced conformational changes of the switch II and alpha helical domains create new possibilities for protein–protein interactions and emphasize the importance of permanent lipid attachment for the conformation and functional tunability of signaling proteins.