Discovering and understanding hidden drug binding sites to combat antibiotic resistance: GPU-accelerated study of TEM-1 beta-lactamase
Year: 2020
Type: other
Abstract: Protein folding is carefully regulated through a network of intra- and intermolecular interactions resulting from amino acid side chains, backbone functional groups, and solvent. Hydrogen bonding is one of the most critical forces stabilizing protein structure. Unnatural modifications to the protein backbone or side chains can affect modulate these interactions and are commonly used to alter the physical and chemical properties of proteins. One important class of modifications are aza-amino acids, which are typically characterized by substitution of the u03b1-carbon with nitrogen. This substitution can result in aza-residues exhibiting restricted conformational flexibility compared to natural amide linkages, making them valuable tools for structural studies and peptidomimetics. Mimetic peptides are indispensable for studying natural proteins including collagen, the most abundant protein in mammals. Collagenu2019s folded structure involves three individual chains intertwining to form a triple helical bundle. Collagenu2019s primary structure is often represented using repeating (Xaa-Yaa-Glycine) triplet sequences; the Xaa and Yaa positions are variable, but glycine is largely conserved. Our group has previously shown substitution of glycine residues with azaglycine in a collagen peptide results in increased triple helix thermal stability. In this work, we demonstrate aza-glycineu2019s effect on the triple helix stability is surprisingly dependent on its neighboring Xaa and Yaa residues. To counteract this, we present a sequence-independent strategy for stabilizing the triple helix using aza-glycine residues as u201cclampsu201d around a central substitution.
Authors: Steven Austin, Wei Yang, Dongsheng Wu
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4213046918