Controlling Biopolymer Phase Networks with Dynamic Chemical Networks Open Access

Young, Seth (Spring 2021)

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Collagen is a phenomenally versatile and dynamic structure necessary for the survival of almost all multicellular life. This protein’s strong intermolecular forces provide physical support while remaining flexible through interspaced flexible elements. Multitudes of approaches have been taken to try and replicate the physical properties of this protein; however, most approaches have failed to capture the flexibility of collagen by solely focusing on developing a strong material without accounting for its dynamics. Utilizing the metastable pyrimidinone chemistry built by Chen et al., we set out to replicate the flexibility of collagen using a C-terminal aldehyde peptide asparagine proline glycine (NPG). This peptide successfully assembles into a fibrillar structure that bundles and eventually twists into a new structure termed ‘ball of yarn.’ In addition, this peptide was found to decrease apoptosis and increase differentiation of neurons in preliminary studies on brain organoids. Synthesis of this was then optimized and adapted to allow for a more expansive synthetic approach to C-terminal aldehyde peptides.

Table of Contents

Table of Contents

Abstract iv

1 Introduction. 1

2 Methods. 3

2.1 Initial Synthesis. 3

2.1.1 Boc-G-OH to Boc-G-Weinreb. 4

2.1.2 Boc-G-OH to HCl-NH2-G-Weinreb. 4

2.1.3 HCl-NH2-G-Weinreb to Boc-PG-Weinreb. 5

2.1.4 Boc-PG-Weinreb to HCl-NH2-PG-Weinreb. 6

2.1.5 HCl-NH2-PG-Weinreb to Fmoc-NPG-Weinreb. 6

2.1.6 Fmoc-NPG-Weinreb to Fmoc-NPG-CHO.. 7

2.1.7 Fmoc-NPG-CHO to NH2-NPG-CHO.. 8

2.2 Characterization. 8

2.2.1 Transmission Electron Microscopy. 8

2.2.2 X-Ray Diffraction. 9

2.2.3 Organoids. 9

2.3 Updated Synthesis. 9

2.3.1 Synthesis of Boc trt Asn Control and General Procedure for EDC Coupling. 9

2.3.2 Reduction of NPG on resin with LAH (2.0 Equivalents Approach) 10

2.3.3 Control Study of the Reduction of Boc-trt-Asn-Weinreb. 11

2.3.4 DIBAL Reduction of NPG.. 12

3 Results. 12

3.1 Synthesis. 12

3.2 Transmission Electron Microscopy (TEM) 13

3.3 X-Ray Diffraction (XRD) 14

3.4 Organoids. 15

3.5 Synthesis Optimization. 16

4 Discussion. 16

4.1 Transmission Electron Microscopy. 17

4.2 X-Ray Diffraction. 19

4.3 Organoids. 19

4.4 Drawbacks of the Initial Synthesis. 20

4.5 Assembly. 21

4.6 Synthesis Optimization. 25

5 Conclusions. 28

6 References. 30

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