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. 2007 Oct 31;129(43):13043-8.
doi: 10.1021/ja073391r. Epub 2007 Oct 6.

An artificial beta-sheet that dimerizes through parallel beta-sheet interactions

Sergiy Levin  1 , James S Nowick
Affiliations

An artificial beta-sheet that dimerizes through parallel beta-sheet interactions

Sergiy Levin et al. J Am Chem Soc. .

Abstract

This Article introduces a simple chemical model of a beta-sheet (artificial beta-sheet) that dimerizes by parallel beta-sheet formation in chloroform solution. The artificial beta-sheet consists of two N-terminally linked peptide strands that are linked with succinic or fumaric acid and blocked along one edge with a hydrogen-bonding template composed of 5-aminoanisic acid hydrazide. The template is connected to one of the peptide strands by a turn unit composed of (S)-2-aminoadipic acid (Aaa). 1H NMR spectroscopic studies show that these artificial beta-sheets fold in CDCl3 solution to form well-defined beta-sheet structures that dimerize through parallel beta-sheet interactions. Most notably, all of these compounds show a rich network of NOEs associated with folding and dimerization. The compounds also exhibit chemical shifts and coupling constants consistent with the formation of folded dimeric beta-sheet structures. The aminoadipic acid unit shows patterns of NOEs and coupling constants consistent with a well-defined turn conformation. The present system represents a significant step toward modeling the type of parallel beta-sheet interactions that occur in protein aggregation.

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Figures

Figure 1
Figure 1
Characteristic NOEs (arrows) in parallel and antiparallel β-sheets. Structures are shown for the alanine dipeptide, with Newman projections shown for the Cβ;–Cα bonds.
Figure 2
Figure 2
Selected NOEs in artificial β-sheet 1a. 800-MHz NOESY spectrum recorded at 10 mM and 268 K in CDCl3 with a 400-ms mixing time. Expansions A–C show intramolecular NOEs; expansions D–F show intermolecular NOEs.,
Figure 3
Figure 3
Key NOEs observed in artificial β-sheet 1a. Red arrows represent intermolecular NOEs; blue arrows represent intramolecular NOEs.
Figure 4
Figure 4
Representative splitting patterns for the aminoadipic acid δ-protons (artificial β-sheet 1c).
Figure 5
Figure 5
Model of the aminoadipic acid turn unit. The global minimum of Ac-Aaa(NHMe)-NMe2 was determined using MacroModel v8.5 with the MMFF* force field and GB/SA CHCl3 solvation. Arrows indicate key NOEs observed for the turn units of 1 and 2a.
Figure 6
Figure 6
Selected NOEs observed for the succinic acid protons of 1a. 800-MHz NOESY spectrum recorded at 10 mM and 268 K in CDCl3 with a 400-ms mixing time.
Scheme 1
Scheme 1
Chart 1
Chart 1
Chart 2
Chart 2
Key NOEs observed for the succinic acid linker unit of 1a.
See this image and copyright information in PMC

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