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. 2023 Jul 4;9(7):1480-1487.
doi: 10.1021/acscentsci.3c00230. eCollection 2023 Jul 26.

Experimental Insights into Conformational Ensembles of Assembled β-Sheet Peptides

Lanlan Yu  1 , Ruonan Wang  1 , Shucong Li  2 , Ufuoma I Kara  3 , Eric C Boerner  3 , Boyuan Chen  3 , Feiyi Zhang  1   4 , Zhongyi Jian  1 , Shuyuan Li  1 , Mingwei Liu  1 , Yang Wang  1 , Shuli Liu  5 , Yanlian Yang  6 , Chen Wang  6 , Wenbo Zhang  1 , Yuxing Yao  7 , Xiaoguang Wang  3   8 , Chenxuan Wang  1
Affiliations

Experimental Insights into Conformational Ensembles of Assembled β-Sheet Peptides

Lanlan Yu et al. ACS Cent Sci. .

Abstract

Deciphering the conformations and interactions of peptides in their assemblies offers a basis for guiding the rational design of peptide-assembled materials. Here we report the use of scanning tunneling microscopy (STM), a single-molecule imaging method with a submolecular resolution, to distinguish 18 types of coexisting conformational substates of the β-strand of the 8-37 segment of human islet amyloid polypeptide (hIAPP 8-37). We analyzed the pairwise peptide-peptide interactions in the hIAPP 8-37 assembly and found 82 interconformation interactions within a free energy difference of 3.40 kBT. Besides hIAPP 8-37, this STM method validates the existence of multiple conformations of other β-sheet peptide assemblies, including mutated hIAPP 8-37 and amyloid-β 42. Overall, the results reported in this work provide single-molecule experimental insights into the conformational ensemble and interpeptide interactions in the β-sheet peptide assembly.

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Conflict of interest statement

The authors declare the following competing financial interest(s): Chenxuan Wang, L.Y., R.W., Chen Wang, Yanlian Yang, W.Z., Shuyuan Li, M.L., and F.Z. are inventors on a pending Chinese patent related to this work filed by the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, and National Center for Nanoscience and Technology (patent no. ZL 2022 1 0848779.7). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Conformational ensemble and interpeptide interactions of hIAPP 8-37. (a) The primary sequence of hIAPP 8-37. (b) A representative STM image of the hIAPP 8-37 assembly. Tunneling conditions: tunneling current 299.1 pA and bias voltage 529.8 mV. (c, d) The separation distance between two adjacent peptide β-strands and the length of peptide β-sheets. (e) STM images showing interpeptide interaction in the hIAPP 8-37 assembly and the percentage of different substates interacting with substate VII (N = 158). The interaction between the same conformational substates (VII–VII) is shown in red. (f) Conformational substates and the intersubstate interactions identified in the hIAPP 8-37 assembly. Representative STM images and length of amino acid residues in the β-strand (AA) for each conformational substate are shown with the circular chord diagram of interpeptide interactions (N = 554). Scale bars: 2 nm.
Figure 2
Figure 2
Conformation ensemble and interpeptide interactions of hIAPP S20G 8-37. (a) The primary sequence of hIAPP S20G 8-37. (b) A representative STM image of the hIAPP S20G 8-37 assembly. Tunneling conditions: tunneling current 299.1 pA and bias voltage 600.0 mV. (c) The separation distance between two adjacent hIAPP S20G 8-37 strands. (d) A comparison of the β-strand lengths of hIAPP 8-37 and hIAPP S20G 8-37. (e) Conformational substates and the intersubstate interactions identified in the hIAPP S20G 8-37 assembly. Representative STM images and length of amino acid residues in the β-strand (AA) for each conformational substate are shown with the circular chord diagram of interpeptide interactions (N = 477). Scale bars: 2 nm.
Figure 3
Figure 3
Single-site mutation modulates hIAPP 8-37 interpeptide interactions. (a, b) The probability of intersubstate interactions in the assembly of hIAPP 8-37 (N = 554) (a) and hIAPP S20G 8-37 (N = 477) (b). (c) P/P′ as a function of offset for hIAPP 8-37 (red) and hIAPP S20G 8-37 (blue). The inset is a scheme showing the offset in interactions between two substates. (d, e) Two-dimensional energy landscape of the hIAPP 8-37 (d) and hIAPP S20G 8-37 (e) interpeptide interactions. (f) A comparison of free energy of homoconformational interactions (diagonal of (d) and (e)) in hIAPP 8-37 and hIAPP S20G 8-37 assemblies.
Figure 4
Figure 4
Conformation ensemble and interpeptide interactions of Aβ42. (a) Conformational ensemble and interpeptide interactions of Aβ42 (N = 460). Representative STM images and lengths of amino acid residues in the β-strand (AA) for each conformational substate are shown with the circular chord diagram of interpeptide interactions. Scale bars: 2 nm. (b–d) A comparison of the number of conformational substates (b), the energy difference of the conformational ensemble (c), and P/P′ at an offset of ±1 (d) of hIAPP 8-37, hIAPP S20G 8-37, and Aβ42.
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