A critical assessment of force field accuracy against NMR data for cyclic peptides containing β-amino acids

Physical Chemistry Chemical Physics : PCCP
C PaissoniM Ghitti

Abstract

Hybrid cyclic α/β-peptides, in which one or more β-amino acids are incorporated into the backbone, are gaining increasing interest as potential therapeutics, thanks to their ability to achieve enhanced binding affinities for a biological target through pre-organization in solution. The in silico prediction of their three dimensional structure through strategies such as MD simulations would substantially advance the rational design process. However, whether the molecular mechanics force fields are accurate in sampling highly constrained cyclopeptides containing β-amino acids remains to be verified. Here, we present a systematic assessment of the ability of 8 widely used force fields to reproduce 79 NMR observables (including chemical shifts and 3J scalar couplings) on five cyclic α/β-peptides that contain the integrin recognition motif isoDGR. Most of the investigated force fields, which include force fields from AMBER, OPLS, CHARMM and GROMOS families, display very good agreement with experimental 3J(HN,Hα), suggesting that MD simulations could be an appropriate tool in the rational design of therapeutic cyclic α-peptides. However, for NMR observables directly related to β-amino acids, we observed a poor agreement with experime...Continue Reading

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Citations

Jan 12, 2021·Chemical Reviews·Jovan DamjanovicYu-Shan Lin
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jasmin DülferCharlotte Uetrecht
May 26, 2021·Physical Chemistry Chemical Physics : PCCP·Xiaochen CuiHai-Feng Chen

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Methods Mentioned

BETA
NMR
X-ray

Software Mentioned

L STD
Metagui
GAMESS
AA
Sparta
BE
AMBER
Maestro 2D sketcher
Metadynamics Exchange
CNS

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