Twists or turns: stabilising alpha vs. beta turns in tetrapeptides

Huy N. Hoang; Timothy A. Hill; Gloria Ruiz-Gómez; Frederik Diness; Jody M. Mason; Chongyang Wu; Giovanni Abbenante; Nicholas E. Shepherd; David P. Fairlie

doi:10.1039/c9sc04153b

Twists or turns: stabilising alpha vs. beta turns in tetrapeptides

Huy N. Hoang, Timothy A. Hill, Gloria Ruiz-Gómez, Frederik Diness, Jody M. Mason, Chongyang Wu, Giovanni Abbenante, Nicholas E. Shepherd, David P. Fairlie

Department of Chemistry

1 Citation (Scopus)

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Abstract

Protein-protein interactions involve hotspots as small as 4 sequential amino acids. Corresponding tetrapeptides have no structure in water. Here we report linking side chains of amino acids X and Z to form 24 cyclic tetrapeptides, cyclo-[XAAZ]-NH₂, and stabilise 14-18 membered rings that mimic different kinds of non-regular secondary structures found in protein hotspots. 2D NMR spectra allowed determination of 3D structures for 14 cyclic tetrapeptides in water. Five formed two (i, i + 3) hydrogen bonds and a beta/gamma (6, 7) or beta (9, 19, 20) turn; eight formed one (i, i + 4) hydrogen bond and twisted into a non-helical (13, 18, 21, 22, 24) or helical (5, 17, 23) alpha turn; one was less structured (15). A beta or gamma turn was favoured for Z = Dab, Orn or Glu due to a χ1 gauche (+) rotamer, while an alpha turn was favoured for Z = Dap (but not X = Dap) due to a gauche (-) rotamer. Surprisingly, an unstructured peptide ARLARLARL could be twisted into a helix when either a helical or non-helical alpha turn (5, 13, 17, 18, 21-24) with Z = Dap was attached to the N-terminus. These structural models provide insights into stability for different turns and twists corresponding to non-regular folds in protein hotspots.

Original language	English
Journal	Chemical Science
Volume	10
Issue number	45
Pages (from-to)	10595-10600
ISSN	2041-6520
DOIs	https://doi.org/10.1039/c9sc04153b
Publication status	Published - 2019

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10.1039/c9sc04153bLicence: CC BY-NC

Twists or turnsFinal published version, 1.5 MBLicence: CC BY-NC

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@article{224fbb4535144be1a4f2fffe7e9f9404,

title = "Twists or turns: stabilising alpha vs. beta turns in tetrapeptides",

abstract = "Protein-protein interactions involve hotspots as small as 4 sequential amino acids. Corresponding tetrapeptides have no structure in water. Here we report linking side chains of amino acids X and Z to form 24 cyclic tetrapeptides, cyclo-[XAAZ]-NH2, and stabilise 14-18 membered rings that mimic different kinds of non-regular secondary structures found in protein hotspots. 2D NMR spectra allowed determination of 3D structures for 14 cyclic tetrapeptides in water. Five formed two (i, i + 3) hydrogen bonds and a beta/gamma (6, 7) or beta (9, 19, 20) turn; eight formed one (i, i + 4) hydrogen bond and twisted into a non-helical (13, 18, 21, 22, 24) or helical (5, 17, 23) alpha turn; one was less structured (15). A beta or gamma turn was favoured for Z = Dab, Orn or Glu due to a χ1 gauche (+) rotamer, while an alpha turn was favoured for Z = Dap (but not X = Dap) due to a gauche (-) rotamer. Surprisingly, an unstructured peptide ARLARLARL could be twisted into a helix when either a helical or non-helical alpha turn (5, 13, 17, 18, 21-24) with Z = Dap was attached to the N-terminus. These structural models provide insights into stability for different turns and twists corresponding to non-regular folds in protein hotspots.",

author = "Hoang, {Huy N.} and Hill, {Timothy A.} and Gloria Ruiz-G{\'o}mez and Frederik Diness and Mason, {Jody M.} and Chongyang Wu and Giovanni Abbenante and Shepherd, {Nicholas E.} and Fairlie, {David P.}",

year = "2019",

doi = "10.1039/c9sc04153b",

language = "English",

volume = "10",

pages = "10595--10600",

journal = "Chemical Science",

issn = "2041-6520",

publisher = "Royal Society of Chemistry",

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TY - JOUR

T1 - Twists or turns

T2 - stabilising alpha vs. beta turns in tetrapeptides

AU - Hoang, Huy N.

AU - Hill, Timothy A.

AU - Ruiz-Gómez, Gloria

AU - Diness, Frederik

AU - Mason, Jody M.

AU - Wu, Chongyang

AU - Abbenante, Giovanni

AU - Shepherd, Nicholas E.

AU - Fairlie, David P.

PY - 2019

Y1 - 2019

N2 - Protein-protein interactions involve hotspots as small as 4 sequential amino acids. Corresponding tetrapeptides have no structure in water. Here we report linking side chains of amino acids X and Z to form 24 cyclic tetrapeptides, cyclo-[XAAZ]-NH2, and stabilise 14-18 membered rings that mimic different kinds of non-regular secondary structures found in protein hotspots. 2D NMR spectra allowed determination of 3D structures for 14 cyclic tetrapeptides in water. Five formed two (i, i + 3) hydrogen bonds and a beta/gamma (6, 7) or beta (9, 19, 20) turn; eight formed one (i, i + 4) hydrogen bond and twisted into a non-helical (13, 18, 21, 22, 24) or helical (5, 17, 23) alpha turn; one was less structured (15). A beta or gamma turn was favoured for Z = Dab, Orn or Glu due to a χ1 gauche (+) rotamer, while an alpha turn was favoured for Z = Dap (but not X = Dap) due to a gauche (-) rotamer. Surprisingly, an unstructured peptide ARLARLARL could be twisted into a helix when either a helical or non-helical alpha turn (5, 13, 17, 18, 21-24) with Z = Dap was attached to the N-terminus. These structural models provide insights into stability for different turns and twists corresponding to non-regular folds in protein hotspots.

AB - Protein-protein interactions involve hotspots as small as 4 sequential amino acids. Corresponding tetrapeptides have no structure in water. Here we report linking side chains of amino acids X and Z to form 24 cyclic tetrapeptides, cyclo-[XAAZ]-NH2, and stabilise 14-18 membered rings that mimic different kinds of non-regular secondary structures found in protein hotspots. 2D NMR spectra allowed determination of 3D structures for 14 cyclic tetrapeptides in water. Five formed two (i, i + 3) hydrogen bonds and a beta/gamma (6, 7) or beta (9, 19, 20) turn; eight formed one (i, i + 4) hydrogen bond and twisted into a non-helical (13, 18, 21, 22, 24) or helical (5, 17, 23) alpha turn; one was less structured (15). A beta or gamma turn was favoured for Z = Dab, Orn or Glu due to a χ1 gauche (+) rotamer, while an alpha turn was favoured for Z = Dap (but not X = Dap) due to a gauche (-) rotamer. Surprisingly, an unstructured peptide ARLARLARL could be twisted into a helix when either a helical or non-helical alpha turn (5, 13, 17, 18, 21-24) with Z = Dap was attached to the N-terminus. These structural models provide insights into stability for different turns and twists corresponding to non-regular folds in protein hotspots.

U2 - 10.1039/c9sc04153b

DO - 10.1039/c9sc04153b

M3 - Journal article

C2 - 32110345

SN - 2041-6520

VL - 10

SP - 10595

EP - 10600

JO - Chemical Science

JF - Chemical Science

IS - 45

ER -

Twists or turns: stabilising alpha vs. beta turns in tetrapeptides

Abstract

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