Design of multi-phase dynamic chemical networks

Abstract

Template-directed polymerization reactions enable the accurate storage and processing of nature's biopolymer information. This mutualistic relationship of nucleic acids and proteins, a network known as life's central dogma, is now marvellously complex, and the progressive steps necessary for creating the initial sequence and chain-length-specific polymer templates are lost to time. Here we design and construct dynamic polymerization networks that exploit metastable prion cross-β phases. Mixed-phase environments have been used for constructing synthetic polymers, but these dynamic phases emerge naturally from the growing peptide oligomers and create environments suitable both to nucleate assembly and select for ordered templates. The resulting templates direct the amplification of a phase containing only chain-length-specific peptide-like oligomers. Such multi-phase biopolymer dynamics reveal pathways for the emergence, self-selection and amplification of chain-length- and possibly sequence-specific biopolymers.

Spontaneous Aminolytic Cyclization and Self‐Assembly of Dipeptide Methyl Esters in Water

“…[18] Peptides and peptide derivatives are attractive building blocks for the fabrication of artificial nanostructures with tremendous biological and nanotechnology applications, arising from their combinatorial diversity and biocompatibility. [19][20][21][22][23][24][25][26] Peptide sequences as short as two or three amino acids have been utilized for nanostructure formation in a sequence dependent manner using linear [27][28][29][30][31][32] or cyclic peptides. [33][34][35][36] Cyclic dipeptides (or diketopiperazines) involve the presentation of amino acid side chain functionality at the exterior of the nanostructure, thus rendering it accessible for interactions and/ or functionalization.…”

Nucleation and Growth of Amino Acid and Peptide Supramolecular Polymers through Liquid–Liquid Phase Separation

“…These challenges primarily originate from the intrinsically dynamic and multiscale hierarchical nature of the self‐assembly process . In general, the structural evolution of supramolecular self‐assemblies is determined by the stability of the different phases and the energy barrier to be overcome to transition between two specific states .…”

Multistep Conformation Selection in Amyloid Assembly

“…11−16 The β-sheets may stack as laminates 11,12 to create a stable cross-β nucleus capable of sustained template-directed propagation. 13,14,16−20 This two-step nucleation 21−23 would place assembly nucleation and propagation in distinct environments and diversify assembly. 22−24 By defining the intermediates in a pH-dependent pathway, we now argue that in addition to electrochemical dynamics, 13−15 a more global consideration of β-sheet facial complementarity 11 contributes dominantly to assembly nucleation.…”

“…For example, previous IE-IR experiments 13 suggested two assembly mechanistic pathways to give a single final structure and that concentration differences could differentially impact the rates of nucleation and propagation much as in polymer synthesis. These conformational transitions, mediated specifically by environmental changes, 20 are not only expected to diversify the range of structures available to model peptide amyloid assemblies but also should be far richer in the complex cellular matrix where so many amyloid diseases are initiated. The nature of the initial nucleation phase may well depend on different cellular protein and membrane surfaces, and understanding the nucleation and propagation mechanisms in cellular environments will become increasingly critical to defining disease etiology.…”