Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2016 Mar 7;52(19):3789-92.
doi: 10.1039/c6cc00273k.

Comparison of design strategies for α-helix backbone modification in a protein tertiary fold

Nathan A Tavenor  1 , Zachary E Reinert  1 , George A Lengyel  1 , Brian D Griffith  1 , W Seth Horne  1
Affiliations
Comparative Study

Comparison of design strategies for α-helix backbone modification in a protein tertiary fold

Nathan A Tavenor et al. Chem Commun (Camb). .

Abstract

We report here the comparison of five classes of unnatural amino acid building blocks for their ability to be accommodated into an α-helix in a protein tertiary fold context. High-resolution structural characterization and analysis of folding thermodynamics yield new insights into the relationship between backbone composition and folding energetics in α-helix mimetics and suggest refined design rules for engineering the backbones of natural sequences.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
(A) Structures of a natural α-residue and five classes of unnatural replacements compared herein. (B, C) Sequence and crystal structure (PDB 2QMT) of Streptococcal protein GB1 (1), the host sequence for helix modification; the crystal structure differs from the wild-type sequence at the N-terminus (MQ in crystal structure vs. DT in 1). (D) Sequences for variants of protein 1 bearing heterogeneous-backbone helices; note, 1–9 are all 56-residue oligomers, but only the helical segment (gray shading in A) is shown. For β3, β2, and chiral Cα-Me-α-residues, the R group in the building block is that of the corresponding natural α-amino acid denoted by the single letter code in the sequence.
Fig. 2
Fig. 2
Comparison of the corresponding α-, β3-, and β2-residues at two sites in the crystal structures of 1–4 (PDB 2QMT, 4KGR, 5HFY, and 5HG2). For position Asn35, chemical structures and distances for putative side-chain to backbone n→π* interactions are shown. In the structure for 1, the side chain carboxamide of Asn35 is flipped relative to the reported structure (PDB 2QMT).
Fig. 3
Fig. 3
Folding free energy at 298 K for proteins 1–8. Error bars show parameter uncertainty from the fits (Fig S4, Table S3).
Fig. 4
Fig. 4
Comparison of the corresponding α-, βcyc-, and Cα-Me-α-residues at position 24 in the crystal structures of 1, 6, and 7 (PDB 2QMT, 4OZB, and 5HI1).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Gellman SH. Acc. Chem. Res. 1998;31:173–180.
    1. Bautista AD, Craig CJ, Harker EA, Schepartz A. Curr. Opin. Chem. Biol. 2007;11:685–692. - PMC - PubMed
    2. Goodman CM, Choi S, Shandler S, DeGrado WF. Nat. Chem. Biol. 2007;3:252–262. - PMC - PubMed
    3. Guichard G, Huc I. Chem. Commun. 2011;47:5933–5941. - PubMed
    4. Horne WS. Expert Opin. Drug Discov. 2011;6:1247–1262. - PubMed
    5. Martinek TA, Fulop F. Chem. Soc. Rev. 2012;41:687–702. - PubMed
    6. Sun J, Zuckermann RN. ACS Nano. 2013;7:4715–4732. - PubMed
    1. Hegedüs Z, Wéber E, Kriston-Pál É, Makra I, Czibula Á, Monostori É, Martinek TA. J. Am. Chem. Soc. 2013;135:16578–16584. - PubMed
    2. Wang PSP, Nguyen JB, Schepartz A. J. Am. Chem. Soc. 2014;136:6810–6813. - PubMed
    3. Checco JW, Kreitler DF, Thomas NC, Belair DG, Rettko NJ, Murphy WL, Forest KT, Gellman SH. Proc. Natl. Acad. Sci. USA. 2015;112:4552–4557. - PMC - PubMed
    1. Mannige RV, Haxton TK, Proulx C, Robertson EJ, Battigelli A, Butterfoss GL, Zuckermann RN, Whitelam S. Nature. 2015;526:415–420. - PubMed
    2. Chandramouli N, Ferrand Y, Lautrette G, Kauffmann B, Mackereth CD, Laguerre M, Dubreuil D, Huc I. Nature Chem. 2015;7:334–341. - PubMed
    3. Collie GW, Pulka-Ziach K, Lombardo CM, Fremaux J, Rosu F, Decossas M, Mauran L, Lambert O, Gabelica V, Mackereth CD, Guichard G. Nature Chem. 2015;7:871–878. - PubMed
    1. Reinert ZE, Horne WS. Org. Biomol. Chem. 2014;12:8796–8802. - PMC - PubMed

Publication types

LinkOut - more resources