Myostatin, an important negative regulator of muscle mass, is a therapeutic target for muscle atrophic disorders such as
muscular dystrophy. Thus, the inhibition of
myostatin presents a strategy to treat these disorders. It has long been established that the
myostatin prodomain is a strong inhibitor of the mature
myostatin, and the minimum
peptide of the prodomain-corresponding to the α1-helix of its lasso-region-responsible for the inhibitory efficiency was defined and characterized as well. Here we show that the minimum
peptide segment based on the growth differentiation
factor 11 (GDF11), which we found to be more helical in its stand-alone solvated stfate than the similar segment of
myostatin, is a promising new base scaffold for inhibitor design. The proposed inhibitory
peptides in their solvated state and in complex with the mature
myostatin were analyzed by in silico molecule modeling supplemented with the electronic circular dichroism spectroscopy measurements. We defined the Gaussian-Mahalanobis mean score to measure the fraction of dihedral angle-pairs close to the desired helical region of the Ramachandran-plot, carried out RING analysis of the
peptide-protein interaction networks and characterized the internal motions of the complexes using our rigid-body segmentation protocol. We identified a variant-11m2-that is sufficiently ordered both in
solvent and within the inhibitory complex, forms a high number of contacts with the binding-pocket and induces such changes in its internal dynamics that lead to a rigidified, permanently locked conformation that traps this
peptide in the binding site. We also showed that the naturally evolved α1-helix has been optimized to simultaneously fulfill two very different roles: to function as a strong binder as well as a good leaving group. It forms an outstanding number of non-covalent interactions with the mature core of
myostatin and maintains the most ordered conformation within the complex, while it induces independent movement of the gate-keeper β-hairpin segment assisting the dissociation and also results in the least-ordered solvated form which provides extra stability for the dissociated state and discourages rebinding.