Evaluation of β‐Amino Acid Replacements in Protein Loops: Effects on Conformational Stability and Structure

Journal Article · Tue Feb 13 00:00:00 EST 2018 · ChemBioChem: a European journal of chemical biology

DOI:https://doi.org/10.1002/cbic.201700580· OSTI ID:1420341

Mortenson, David E. ^[1]; Kreitler, Dale F. ^[1]; Thomas, Nicole C. ^[1]; Guzei, Ilia A. ^[1]; Gellman, Samuel H. ^[1]; Forest, Katrina T. ^[2]

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1. Department of Chemistry University of Wisconsin-Madison 1101 University Avenue Madison WI 53706 USA
2. Departments of Chemistry and Bacteriology University of Wisconsin-Madison 1550 Linden Drive Madison WI 53706 USA

Abstract

β‐Amino acids have a backbone that is expanded by one carbon atom relative to α‐amino acids, and β residues have been investigated as subunits in protein‐like molecules that adopt discrete and predictable conformations. Two classes of β residue have been widely explored in the context of generating α‐helix‐like conformations: β ³ ‐amino acids, which are homologous to α‐amino acids and bear a side chain on the backbone carbon adjacent to nitrogen, and residues constrained by a five‐membered ring, such the one derived from trans ‐2‐aminocyclopentanecarboxylic acid (ACPC). Substitution of α residues with their β ³  homologues within an α‐helix‐forming sequence generally causes a decrease in conformational stability. Use of a ring‐constrained β residue, however, can offset the destabilizing effect of α→β substitution. Here we extend the study of α→β substitutions, involving both β ³ and ACPC residues, to short loops within a small tertiary motif. We start from previously reported variants of the Pin1 WW domain that contain a two‐, three‐, or four‐residue β‐hairpin loop, and we evaluate α→β replacements at each loop position for each variant. By referral to the ϕ , ψ angles of the native structure, one can choose a stereochemically appropriate ACPC residue. Use of such logically chosen ACPC residues enhances conformational stability in several cases. Crystal structures of three β‐containing Pin1 WW domain variants show that a native‐like tertiary structure is maintained in each case.

• Sponsoring Organization: USDOE
• Grant/Contract Number: AC02-06CH11357
• OSTI ID: 1420341
• Alternate ID(s): OSTI ID: 1499740
• Journal Information: ChemBioChem: a European journal of chemical biology, Journal Name: ChemBioChem: a European journal of chemical biology Journal Issue: 6 Vol. 19; ISSN 1439-4227
• Publisher: Wiley Blackwell (John Wiley & Sons)
• Country of Publication: France
• Language: English