Nanostructure Design Using Protein Building Blocks Enhanced by Conformationally Constrained Synthetic Residues
Increasing efforts are being invested in the construction of nanostructures with desired shapes and physical and chemical properties. Our strategy involves nanostructure design using naturally occurring protein building blocks. Inspection of the protein structural database (PDB) reveals the richness of the conformations, shapes, and chemistries of proteins and their building blocks. To increase the population of the native fold in the selected building block, we mutate natural residues by engineered, constrained residues that restrict the conformational freedom at the targeted site and have favorable interactions, geometry, and size. Here, as a model system, we construct nanotubes using building blocks from left-handed β-helices which are commonly occurring repeat protein architectures. We pick two-turn β-helical segments, duplicate and stack them, and using all-atom molecular dynamics simulations (MD) with explicit solvent probe the structural stability of these nanotubular structures as indicated by their capacity to retain the initial organization and their conformational dynamics. Comparison of the results for the wild-type and mutated sequences shows that the introduction of the conformationally restricted 1-aminocyclopropanecarboxylic acid (Ac3c) residue in loop regions greatly enhances the stability of β-helix nanotubes. The Ac3c geometrical confinement effect is sequence-specific and position-specific. The achievement of high stability of nanotubular structures originates not only from the reduction of mobility at the mutation site induced by Ac3c but also from stabilizing association forces between building blocks such as hydrogen bonds and hydrophobic contacts. For the selected synthetic residue, similar size, hydrophobicity, and backbone conformational tendencies are desirable as in the Ac3c.
Zheng, Jie, "Nanostructure Design Using Protein Building Blocks Enhanced by Conformationally Constrained Synthetic Residues" (2007). Chemical and Biomolecular Engineering Faculty Research. 270.