Thermodynamic origin of α-helix stabilization by side-chain cross-links in a small protein. Issue 24 (23rd March 2016)

• Record Type: Journal Article
• Authors: Haney, Conor M.; Werner, Halina M.; McKay, James J.; Horne, W. Seth
• Is Part Of: Organic & biomolecular chemistry. Volume 14:Issue 24(2016)
• Page Start: 5768
• Page End: 5773
• Publication Date: 2016-03-23
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/c6ob00475j
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : Side-chain cyclization has a consistent effect on protein folding energetics, and the identity of the cross-linking moiety determines the magnitude of stabilization. Abstract : Peptide cross-linking has been widely explored as a means of constraining short sequences into stable folded conformations, most commonly α-helices. The prevailing hypothesis for the origin of helix stabilization is an entropic effect resulting from backbone pre-organization; however, obtaining direct evidence bearing on this hypothesis is challenging. Here, we compare the folding thermodynamics of a small helix-rich protein domain and analogues containing one of three common cross-linking motifs. Analysis of the folding free energy landscapes of linear vs . cyclized species reveal consistent trends in the effect of cyclization on folding energetics, as well as subtle differences based on the chemistry of the cross link. Stabilization in all three systems arises entirely from a reduction in the entropic penalty of folding that more than compensates for an enthalpic destabilization of the folded state.