Evaluating β-turn mimics as β-sheet folding nucleators

Fuller, AA and Du, D and Liu, F and Davoren, JE and Bhabha, G and Kroon, G and Case, DA and Dyson, HJ and Powers, ET and Wipf, P and Gruebele, M and Kelly, JW (2009) Evaluating β-turn mimics as β-sheet folding nucleators. Proceedings of the National Academy of Sciences of the United States of America, 106 (27). 11067 - 11072. ISSN 0027-8424

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Abstract

β-Turns are common conformations that enable proteins to adopt globular structures, and their formation is often rate limiting for folding. β-Turn mimics, molecules that replace the i + 1 and i + 2 amino acid residues of a β-turn, are envisioned to act as folding nucleators by preorganizing the pendant polypeptide chains, thereby lowering the activation barrier for β-sheet formation. However, the crucial kinetic experiments to demonstrate that β-turn mimics can act as strong nucleators in the context of a cooperatively folding protein have not been reported. We have incorporated 6 β-turn mimics simulating varied β-turn types in place of 2 residues in an engineered β-turn 1 or β-bulge turn 1 of the Pin 1WWdomain, a three-stranded β-sheet protein. We present 2 lines of kinetic evidence that the inclusion of β-turn mimics alters β-sheet folding rates, enabling us to classify β-turn mimics into 3 categories: those that are weak nucleators but permit Pin WW folding, native-like nucleators, and strong nucleators. Strong nucleators accelerate folding relative to WW domains incorporating all β-amino acid sequences. A solution NMR structure reveals that the native PinWW β-sheet structure is retained upon incorporating a strong E-olefin nucleator. These β-turn mimics can now be used to interrogate protein folding transition state structures and the 2 kinetic analyses presented can be used to assess the nucleation capacity of other β-turn mimics.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Fuller, AA Du, D Liu, F Davoren, JE Bhabha, G Kroon, G Case, DA Dyson, HJ Powers, ET Wipf, P pwipf@pitt.edu PWIPF Gruebele, M Kelly, JW
Date:	7 July 2009
Date Type:	Publication
Journal or Publication Title:	Proceedings of the National Academy of Sciences of the United States of America
Volume:	106
Number:	27
Page Range:	11067 - 11072
DOI or Unique Handle:	10.1073/pnas.0813012106
Schools and Programs:	Dietrich School of Arts and Sciences > Chemistry
Refereed:	Yes
ISSN:	0027-8424
MeSH Headings:	Amino Acid Sequence; Humans; Kinetics; Molecular Mimicry; Molecular Sequence Data; Mutant Proteins; Peptidylprolyl Isomerase--chemistry; Protein Stability; Protein Structure, Secondary; Protein Structure, Tertiary; Solutions; Thermodynamics
Other ID:	NLM PMC2708776
PubMed Central ID:	PMC2708776
PubMed ID:	19541614
Date Deposited:	07 Jun 2013 20:00
Last Modified:	26 Sep 2022 16:49
URI:	http://d-scholarship.pitt.edu/id/eprint/18850

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