Disorder outpacing order: amyloid-inspired peptide with guanidinium motifs to dictate dynamic self-assembly vs liquid- liquid phase separation Nimisha A. Mavlankar and Asish Pal* Chemical Biology Unit, Institute of Nano Science and Technology, India E-mail address: nimisha.ph19215@inst.ac.in Supramolecular assemblies are indispensable to orchestrate proper functioning of living systems. A precise control over the ordered assembly, spatiotemporally and structurally enables efficient activity of the involved assemblies. Such self-organization can be found in amyloids by virtue of its nucleation driven polymerization. Various kinetically trapped states can be accessed by developing a minimalist amyloid mimic model system to find answers to complex challenges of systems chemistry and biology like secondary nucleation. However, addressing the disorder and misfolding of such proteins is an equally essential fundamental question to unravel the mystery of origin of life via hallmarks of living viz. compartmentalization, self-replication and metabolism. This calls for development of a handle that can tweak order-disorder molecular arrangement in a single system on demand. In this work, utilizing like charge ion-pairing ability of guanidinium cations we have developed positional isomers of an amyloid-inspired minimalistic peptide amphiphile involving pathway-driven stimuli-responsive self-assembly. Herein, we study the sequence-structure relationship and stimuli-responsiveness of the peptides for their potential towards self-assembly vs phase separation/coacervate formation. The self-assembled system shows transient sheet formation and kinetically controlled nanofiber formation with secondary nucleation. The kinetic nanofiber states can be made mechanically robust by a functional polydopamine coating, whereas chemical trigger can demonstrate co-existing fibrils and droplets in same system. Sequence scrambling of the amyloid-inspired peptide induces disorder and can exclusively facilitate coacervate formation arising from re-entrant phase separation. Such compartmentalized systems can be further studied for its mobility, growth and division. Also, strategies to trap kinetic states can be explored to prevent autocatalytic amplification of aggregate mass that complicates diseases arising from protein misfolding and aggregation. References 1. N. A. Mavlankar, A. K. Awasthi, M. K. Pradhan, A. Srivastava and A. Pal (Manuscript under preparation). N. A. Mavlankar, A. K. Awasthi, J. Ralhan and A. Pal, ChemNanoMat., 2022 , DOI: 10.1002/cnma.202200368. 2. T.C.T. Michaels, A. Šarić, S. Curk, K. Bernfur, P. Arosio, G. Meisl, A.J. Dear, S. I. A. Cohen, C.M. Dobson, M. Vendruscolo, S. Linse and T. P. J. Knowles, Nat. Chem . 2020 , 12, 445–451. DOI: 10.1038/s41557-020-0452-1.
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