The structural organization of the B1 domain of streptococcal protein G (PGA) has been probed using molecular dynamics simulations, with a particular emphasis on the role of the solvent exposed Ile6 residue. In addition to the native protein (WT-PGA), three single-mutants (I6G-PGA, I6F-PGA, and I6T-PGA), one double-mutant (I6T,T53G-PGA), and three isolated peptide fragments (corresponding to the helix and the two β-hairpins) were studied in the presence of explicit water molecules. Comparative analysis of the various systems showed that the level of perturbation was directly related to the hydrophobicity and the size of the side chain of residue 6, the internal rigidity of the proteins decreasing in the order I6T-PGA > I6G-PGA > WT-PGA > I6F-PGA. The results emphasized the importance of residue 6 in controlling both the integrity of the sheet's surface and the orientation of the helix in relation to the sheet by modulation of surface/core interactions. The effects of mutations were delocalized across the structure, and glycine residues, in particular, absorbed most of the introduced strain. A qualitative structural decomposition of the native fold into elementary building-blocks was achieved using principal component analysis and mechanical response matrices. Within this framework, internal motions of the protein were described as coordinated articulations of these structural units, mutations affecting mostly the amplitude of the motions rather than the structure/location of the building-blocks. Analysis of the isolated peptidic fragments suggested that packing did not play a determinant role in defining the elementary building-blocks, but that chain topology was mostly responsible.