Molecular dynamics and computational alanine scanning techniques have been used to investigate G proteins in their inactive state (the Galpha(i1)beta(1)gamma(2) heterotrimer) as well as in their empty and monomeric active states (Galpha(i1) subunit). We find that: (i) the residue Q204 of Galpha(i1) plays a key role for binding Gbeta(1)gamma(2) and is classified among the most relevant in the interaction with a key cellular partner, the so-called regulator of G protein signaling protein. The mutation of this residue to L, which is observed in a variety of diseases, provides still fair stability to the inactive state because of the formation of van der Waals interactions. (ii) The empty state turns out to adopt some structural features of the active one, including a previously unrecognized rearrangement of a key residue (K46). (iii) The so-called Switch IV region increases its mobility on passing from the empty to the active state, and, even more, to the inactive state. Such change in mobility could be important for its several structural and functional roles. (iv) A large scale motion of the helical domain in the inactive state might be important for GDP release upon activation by GPCR, consistently with experimental data.
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