Dissecting the energetics of protein α-helix C-cap termination through chemical protein synthesis

Duhee Bang, Alexey V. Gribenko, Valentina Tereshko, Anthony A. Kossiakoff, Stephen B. Kent, George I. Makhatadze

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54 Citations (Scopus)


The α-helix is a fundamental protein structural motif and is frequently terminated by a glycine residue. Explanations for the predominance of glycine at the C-cap terminal portions of α-helices have invoked uniquely favorable energetics of this residue in a left-handed conformation or enhanced solvation of the peptide backbone because of the absence of a side chain. Attempts to quantify the contributions of these two effects have been made previously, but the issue remains unresolved. Here we have used chemical protein synthesis to dissect the energetic basis of α-helix termination by comparing a series of ubiquitin variants containing an L-amino acid or the corresponding D-amino acid at the C-cap Gly35 position. D-Amino acids can adopt a left-handed conformation without energetic penalty, so the contributions of conformational strain and backbone solvation can thus be separated. Analysis of the thermodynamic data revealed that the preference for glycine at the C′ position of a helix is predominantly a conformational effect.

Original languageEnglish
Pages (from-to)139-143
Number of pages5
JournalNature Chemical Biology
Issue number3
Publication statusPublished - 2006 Mar

Bibliographical note

Funding Information:
This research was supported by the US Department of Energy Genomes to Life Genomics Program grant DE-FG02-04ER63786 (to S.B.K.), the US National Science Foundation Materials Research Science and Engineering Centers Program at the University of Chicago (grant DMR-0213745), and by US National Institutes of Health grant GM54537 (to G.I.M.). Use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38. Portions of this work were performed at the Industrial Macromolecular Crystallography Association (IMCA-CAT) and at the DuPont-Northwestern-Dow Collaborative Access Team (DND-CAT) located in 17ID and 5ID, respectively, of the Advanced Photon Source. Use of the IMCA-CAT was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with the Center for Advanced Radiation Sources at the University of Chicago. DND-CAT is supported by the E.I. DuPont de Nemours & Co., The Dow Chemical Company, the US National Science Foundation through grant DMR-9304725 and the State of Illinois through the Department of Commerce and the Board of Higher Education grant IBHE HECA NWU 96.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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