Mutually exclusive folding proteins are a class of multidomain proteins in which the host domain remains folded while the guest domain is unfolded, and both domains achieve exchange of their folding status by a mutual exclusive folding (MEF) process. We carried out conventional and targeted molecular dynamics simulations for the mutually exclusive folding protein of GL5/I27 to address the MEF transition mechanisms. We constructed two starting models and two targeted models, i.e., the starting models GL5/I27-S and GL5/I27-ST in which the first model involves the host domain GL5 and the secondary-structure unfolded guest domain I27-S, while the second model involves the host domain GL5 and the secondary/tertiary-structure extending guest domain I27-ST, and the target models GL5-S/I27 and GL5-ST/I27 in which GL5-S and GL5-ST represent the secondary-structure unfolding and the secondary/tertiary-structure extending, respectively. We investigated four MEF transition processes from both starting models to both target models. Based on structural changes and the variations of the radius of gyration (Rg
) and the fractions of native contacts (Q
), the formation of the secondary structure of the I27-guest domain induces significant extending of the GL5-host domain; but the primary shrinking of the tertiary structure of the I27-guest domain causes insignificant extending of the GL5-host domain during the processes. The results indicate that only formation of the secondary structure in the I27-guest domain provides the main driving force for the mutually exclusive folding/unfolding between the I27-guest and GL5-host domains. A special structure as an intermediate with both host and guest domains being folded at the same time was found, which was suggested by the experiment. The analysis of hydrogen bonds and correlation motions supported the studied transition mechanism with the dynamical “tug-of-war” phenomenon.
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