Bilingual Peptide Nucleic Acids: Encoding the Languages of Nucleic Acids and Proteins in a Single Self-Assembling Biopolymer

Abstract

Nucleic acids and proteins are the fundamental biopolymers that support all life on Earth. Nucleic acids store large amounts of information in nucleobase sequences while peptides and proteins utilize diverse amino acid functional groups to adopt complex structures and perform wide-ranging activities. Although nature has evolved machinery to read the nucleic acid code and translate it into amino acid code, the extant biopolymers are restricted to encoding amino acid or nucleotide sequences separately, limiting their potential applications in medicine and biotechnology. Here we describe the design, synthesis, and stimuli-responsive assembly behavior of a bilingual biopolymer that integrates both amino acid and nucleobase sequences into a single peptide nucleic acid (PNA) scaffold to enable tunable storage and retrieval of tertiary structural behavior and programmable molecular recognition capabilities. Incorporation of a defined sequence of amino acid side-chains along the PNA backbone yields amphiphiles having a "protein code" that directs self-assembly into micellar architectures in aqueous conditions. However, these amphiphiles also carry a "nucleotide code" such that subsequent introduction of a complementary RNA strand induces a sequence-specific disruption of assemblies through hybridization. Together, these properties establish bilingual PNA as a powerful biopolymer that combines two information systems to harness structural responsiveness and sequence recognition. The PNA scaffold and our synthetic system are highly generalizable, enabling fabrication of a wide array of user-defined peptide and nucleotide sequence combinations for diverse future biomedical and nanotechnology applications.

DNA‐Intercalative Platinum Anticancer Complexes Photoactivated by Visible Light

“…1,8-Naphthalimide ligands L1-L3 were prepared for comparison using modified literature methods (Figures S8-S14). [12] All complexes display a high-energy band at around 260 nm, and an absorption maximum at around 300 nm (Figure S15a, Table S1). A shoulder at around 340 nm is observed for 1 and 2, and an intense band at 450 nm for 3.…”

Synergistic DNA‐ and Protein‐Based Recognition Promote an RNA‐Templated Bio‐orthogonal Reaction

“…This proximity‐induced reaction highlights the potential of structure‐based design in the development of such modular assemblies, particularly given the growing number of available protein/oligonucleotide complex structures [29,30] . Moreover, this expands both the complexity and functional spectrum of recent efforts towards chimeric molecules utilizing peptide and oligonucleotide features [31–36] . Taken together, our work serves as a proof‐of‐concept for the structure‐based design of peptide‐DNA conjugates possessing the ability to assemble into structurally‐defined complexes.…”

“…[ 29 , 30 ] Moreover, this expands both the complexity and functional spectrum of recent efforts towards chimeric molecules utilizing peptide and oligonucleotide features. [ 31 , 32 , 33 , 34 , 35 , 36 ] Taken together, our work serves as a proof‐of‐concept for the structure‐based design of peptide‐DNA conjugates possessing the ability to assemble into structurally‐defined complexes. Such systems can open the door to novel functional biomolecular assemblies.…”

Modular self-assembly of gamma-modified peptide nucleic acids in organic solvent mixtures

“…Therefore, future studies are needed to investigate additional structural motifs and the effects of type and density of gamma functionalization on these systems to expand toward a three-dimensional architectural space. One example of this includes recent work from the Heemstra group on the selfassembly of micellar architecture using γPNA with specific amino acid γ-modifications showing the capability to encode bilingual behavior through protein and nucleobase codes toward more complex nanoarchitectures 66 . In this work, we have also demonstrated that, while the formation of hybrid γPNA-DNA nanostructures would be primarily driven by Watson-Crick base pairing, the structural morphology may be the result of a combination of effects.…”