Engineering new materials that control specific biomolecular transport will be central to numerous technologies including biosensors, bioseparations, and tissue engineering. Natural systems such as nuclear pores routinely regulate molecular transport with remarkable specificity (&gt;99.9% of proteins rejected) and speed (1,000 proteins per second per pore), but the biophysical mechanisms underlying selective nuclear transport remain unclear. The central channel of the nuclear pore is filled with a disordered matrix of nucleoporin proteins, which inspired the development of a selective transport model based on protein binding, diffusion, and solubility in a polymer network. The model predicts two key principles for selective biomolecular transport by a polymer network: (1) entropic repulsion of non-interacting molecules and (2) affinity-mediated permeation of interacting molecules through a walking mechanism.<br/><br/>These key principles are manifest in hierarchical polymer hydrogels that replicate the selective transport function of nuclear pore proteins. First, engineered recombinant nucleoporin-like polypeptides (NLPs) consist of a minimal consensus repeat sequence derived from natural nucleoporins and associative domains that promote gel formation. NLP gels demonstrate enhanced selective permeability in comparison to nucleoporins and enable systematic studies of protein sequence–transport property relationships. Second, synthetic bioinspired affinity gels (BAGs) consist of antibody-binding peptides embedded in a chemically crosslinked poly(ethylene glycol) network. BAGs are used to demonstrate selective transport of a specific monoclonal antibody from a mixture of polyclonal antibodies. Biophysical characterization of NLPs and BAGs using small-angle neutron scattering and fluorescence microscopy reveals the importance of entropic size exclusion, moderate binding affinity, and bound-state diffusion processes in selective hydrogel permeability and transport, in agreement with predictions of the selective transport model. Overall, this work presents a new paradigm for selective transport that critically enables the design of polymer hydrogels to control the transport of multi-receptor biomolecules including therapeutic proteins, immunoglobulins, and broad classes of biotoxins.

Engineering hierarchical polymers to control biomolecular transport

256th National Meeting (2018)

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