title: Stereoelectronic and steric effects in side chains preorganize a protein main chain.
abstract: Preorganization is shown to endow a protein with extraordinary conformational stability. This preorganization is achieved by installing side-chain substituents that impose stereoelectronic and steric effects that restrict main-chain torsion angles. Replacing proline residues in (ProProGly)(7) collagen strands with 4-fluoroproline and 4-methylproline leads to the most stable known triple helices, having T ( m ) values that are increased by > 50 degrees C. Differential scanning calorimetry data indicate an entropic basis to the hyperstability, as expected from an origin in preorganization. Structural data at a resolution of 1.21 A reveal a prototypical triple helix with insignificant deviations to its main chain, even though 2/3 of the residues are nonnatural. Thus, preorganization of a main chain by subtle changes to side chains can confer extraordinary conformational stability upon a protein without perturbing its structure.
authors.affiliation: Department of Chemistry, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Shoulders
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Satyshur
authors.forename: Katrina T
authors.initials: KT
authors.lastname: Forest
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Raines
mesh_terms: D000595:Amino Acid Sequence; D003094:Collagen / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004355:Drug Stability; D004581:Electronics; D008958:Models, Molecular; D008968:Molecular Conformation; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D013237:Stereoisomerism
chemical_list: C474411:4-methylproline; D011506:Proteins; C431803:fluoro-proline; D003094:Collagen; D011392:Proline