Structural and Spectroscopic Properties of Assemblies of Self-Replicating Peptide Macrocycles

Abstract

Self-replication at the molecular level is often seen as essential to the early origins of life. Recently a mechanism of self-replication has been discovered in which replicator self-assembly drives the process. We have studied one of the examples of such self-assembling self-replicating molecules to a high level of structural detail using a combination of computational and spectroscopic techniques. Molecular Dynamics simulations of self-assembled stacks of peptide-derived replicators provide insights into the structural characteristics of the system and serve as the basis for semiempirical calculations of the UV–vis, circular dichroism (CD) and infrared (IR) absorption spectra that reflect the chiral organization and peptide secondary structure of the stacks. Two proposed structural models are tested by comparing calculated spectra to experimental data from electron microscopy, CD and IR spectroscopy, resulting in a better insight into the specific supramolecular interactions that lead to self-replication. Specifically, we find a cooperative self-assembly process in which β-sheet formation leads to well-organized structures, while also the aromatic core of the macrocycles plays an important role in the stability of the resulting fibers.

Controlling Supramolecular Plasticity through Stoichiometry

“…In order to probe whether interactions between 1 and 4 can indeed give rise to new self-assembling species, we prepared a series of DCLs containing the same total amount of building blocks ([1] + [4] = 2.0 mM) with increasing molar ratios of 4, ranging from 0 to 100 mol%. The libraries were stirred at 1200 rpm at room temperature and their composition was monitored with UPLC-MS (Supplemental Information, Sections 2.2.1 and 2.3.)…”

“…In order to obtain insight into the supramolecular structure of the two macrocycles in the native (solution) state, we monitored their selfassembly process with SAXS. Two DCLs were prepared from dithiol monomers under identical conditions (50 mM phosphate buffer, pH = 8.2, [1] + [4] = 2.0 mM, 1200 rpm stirring rate); the first composed of both building blocks ([1]: [4] = 2:1) whereas the second one was composed only of 1. The temporal evolution of the two systems showed remarkable differences: The SAXS profile of the DCL leading to the formation of 1442 ( Figure 3A), showed a characteristic q -1 dependence of the intensity in the 0.1 nm -1 < q -1 < 1 nm -1 region, indicative of the formation of fibers with a diameter of ca.…”

“…In a non-agitated, partially oxidized DCL of 1 octamer formation is very slow, whereas seeding of this sample with a small amount of pre-formed 18 results in fast octamer formation. 47 In contrast, in a slightly oxidized, non-agitated mixture of 1 and 4 ([1] + [4] = 2.0 mM, [1]: [4] = 2:1), fast autonomous conversion (70 mol% hexamer in 50 minutes) into 1442 was observed ( Figure S72). This result showed that the non-catalyzed reaction is very fast leaving little room for autocatalysis.…”

“…Until recently supramolecular chemistry 1,2,[11][12][13][3][4][5][6][7][8][9][10] has followed a different paradigm. Constructing a specific supramolecular assembly has traditionally required it to be the thermodynamically most stable structure.…”

Controlling Supramolecular Plasticity through Stoichiometry

“…Cheng, C., McGonigal, P.R., Schneebeli, S.T., Li, H., Vermeulen, N.A., Ke, C., and Stoddart, J.F. (2015). An artificial molecular pump.…”