Tailoring Hierarchical Structure and Rare Earth Affinity of Compositionally Identical Polymers via Sequence Control

Abstract

Macromolecule sequence, structure, and function are inherently intertwined. While well-established relationships exist in proteins, they are more challenging to define for synthetic polymer nanoparticles due to their molecular weight, sequence, and conformational dispersities. To explore the impact of sequence on nanoparticle structure, we synthesized a set of 16 compositionally identical, sequence-controlled polymers with distinct monomer patterning of dimethyl acrylamide and a bioinspired, structure-driving di(phenylalanine) acrylamide (FF). Sequence control was achieved through multiblock polymerizations, yielding unique ensembles of polymer sequences which were simulated by kinetic Monte Carlo simulations. Systematic analysis of the global (tertiary-and quaternary-like) structure in this amphiphilic copolymer series revealed the effect of multiple sequence descriptors: the number of domains, the hydropathy of terminal domains, and the patchiness (density) of FF within a domain, each of which impacted both chain collapse and the distribution of single-and multichain assemblies. Furthermore, both the conformational freedom of chain segments and local-scale, β-sheet-like interactions were sensitive to the patchiness of FF. To connect sequence, structure, and target function, we evaluated an additional series of nine sequence-controlled copolymers as sequestrants for rare earth elements (REEs) by incorporating a functional acrylic acid monomer into select polymer scaffolds. We identified key sequence variables that influence the binding affinity, capacity, and selectivity of the polymers for REEs. Collectively, these results highlight the potential of and boundaries of sequence control via multiblock polymerizations to drive primary sequence ensembles hierarchical structures, and ultimately the functionality of compositionally identical polymeric materials.

Defining Structure-Function Relationships of Amphiphilic Excipients Enables Rational Design of Ultra-Stable Biopharmaceuticals

“…Monte Carlo simulations have emerged as a powerful tool to understand the composition of individual chains within a polymerization. 21,34,35 In particular, we noticed that at low molecular weights individual polymer chains deviate substantially from the stoichiometrically ideal copolymer composition. 36 To explore this characteristic among the MoNi variants in our study, monomer ratios, reactivity ratios, and dispersities were used to simulate each polymerization at a given molecular weight with a previously published Monte Carlo simulation package, Compositional Drift (Figures S13-18).…”

“…4,8,9 This work was one of the first examples of screening polymer composition to discover new functionality, contributing to the now growing field of high-throughput copolymer discovery. [14][15][16][17][18][19][20][21] These ongoing efforts have seen tremendous success by leveraging the vast chemical space that can be realized by simply combining chemically distinct monomers at different compositional ratios; however, other polymer properties such as molecular weight, dispersity, and end-group functionality have been neglected in these screening investigations. There is a growing appreciation for the importance of these seemingly minor polymer characteristics, and indeed end-group functionality has recently been highlighted as a driver of polymer-protein and polymer-interface interactions.…”

“…[22][23][24][25][26][27][28] Moreover, new studies which simulate individual polymer chains highlight that even within systems of compositionally identical polymers, there can be significant differences between structure and function. 21 With regards to polyacrylamide excipients, there exists a unique opportunity to further characterize the impact of molecular weight, dispersity, and end-group functionality on protein stability and to elucidate mechanisms behind these emergent structure-function relationships.…”

Leveraging Triphenylphosphine-Containing Polymers to Explore Design Principles for Protein-Mimetic Catalysts

“…Using this as inspiration, we sought to understand the impact of the addition of structural elements (i.e., β-sheet-like and electrostatic interactions) on the observed catalytic profile. A di­(phenylalanine) acrylamide monomer (FF, Figures a, S28–S30, and Scheme S2) has been previously observed to imbue local (secondary-like) and global (tertiary- and quaternary-like) structures into polymer systems, , and these structural elements can impact functionality, such as metal binding . Although di­(phenylalanine)-driven assembly is primarily achieved in aqueous media, assembly of di­(phenylalanine) dipeptides has been observed in mixtures of organic solvents including DMF. , This suggests that FF could drive intramolecular interactions within polymer catalysts in aqueous:organic solvent mixtures.…”

Leveraging Triphenylphosphine-Containing Polymers to Explore Design Principles for Protein-Mimetic Catalysts

“…A di(phenylalanine) acrylamide monomer (FF, Figure 3a, S26-S28, Scheme S1) has been previously observed to imbue local (secondary-like) and global (tertiary and quaternary-like) structure into polymer systems, 20,33 and these structural elements can impact functionality, such as metal binding. 34 Although di(phenylalanine)-driven assembly is primarily achieved in aqueous media, assembly of di(phenylalanine) dipeptides has been observed in mixtures of organic solvents including DMF. 35,36 This suggests that FF could drive intramolecular interactions within polymer catalysts in aqueous:organic solvent mixtures.…”