Industrial Molecular Engineering of Nucleic Acids and Proteins

Industrial molecular engineering harnesses advances in synthetic biology, protein chemistry and nucleic acid manipulation to create bespoke biomolecules and streamline their manufacture. On the nucleic acid side, programmable systems—such as RNA-guided nucleases and engineered polymerases—enable precise genome editing, rapid diagnostics and the synthesis of non-natural genetic polymers. In parallel, protein engineering has matured through high-throughput stability mapping and the development of green synthesis platforms for peptides and proteins. Together, these capabilities support the scalable production of enzymes, therapeutic proteins, peptide-based materials and diagnostic reagents under environmentally benign conditions, replacing complex multistep chemical routes with efficient biocatalytic processes.

Research from Nature Portfolio

Recent work has demonstrated a radically accelerated screen for protein folding thermodynamics. By linking each variant’s cDNA to its folded state via controlled proteolysis and deep sequencing, researchers have measured folding free energies for nearly one million single-site mutants in a one-week experiment. This atlas of stability data reveals unexpected long-range couplings, informs the divergence between evolutionary conservation and thermodynamic preferences, and provides a foundation for the design of more stable enzymes and binding proteins. In the field of peptide manufacture, a novel solid-phase protocol has eliminated all solvent-intensive wash steps by exploiting headspace evaporation of deprotection base with directed gas flow. Applied to challenging sequences, this method reduces base consumption by over 80% and solvent waste by up to 95% without sacrificing purity, representing a step-change in commercial peptide synthesis. Separately, a new class of carboxylate-protecting groups based on cyanosulfurylides has been introduced to suppress aspartimide formation. These zwitterionic masks enhance solubility and stability during assembly, are compatible with standard Fmoc chemistry, and can be rapidly removed under mild aqueous conditions. Their adoption solves a longstanding bottleneck in the synthesis of aspartate-rich sequences and facilitates access to complex peptide and protein targets.

Industrial Molecular Engineering of Nucleic Acids and Proteins publication trend

The graph below shows the total number of articles in industrial molecular engineering of nucleic acids and proteins across all publications each year (not limited to Nature Index journals).

Technical terms

cDNA display proteolysis: A massively parallel assay linking each protein variant’s encoding cDNA to its folding stability by selective protease treatment and sequencing.

Solid-phase peptide synthesis (SPPS): An iterative method of assembling peptides on a resin support, involving cycles of deprotection, coupling and washing.

Fmoc: A base-labile protecting group (9-fluorenylmethoxycarbonyl) used to mask amino termini during SPPS.

Native chemical ligation (NCL): A chemoselective reaction joining unprotected peptides via a thioester intermediate followed by S→N acyl transfer to form a native peptide bond.

Cyano­sulfurylide protecting group: A carboxylate-masking moiety that suppresses aspartimide formation and is removed under mild oxidative conditions.

Relaxase: An enzyme that nicks a plasmid at its origin of transfer and remains covalently attached to the single strand during conjugation, facilitating DNA translocation.

Nanopore sensing: A single-molecule technique where ionic current changes through a nanopore report on the passage and conformational state of biomolecules.

Fluorescent-protein cassette: A genetic construct encoding a fluorescent reporter along with regulatory and selectable elements for insertion into host genomes or plasmids.

References

1. Mega-scale experimental analysis of protein folding stability in biology and design. Nature (2023).
2. Total wash elimination for solid phase peptide synthesis. Nature Communications (2023).
3. Prevention of aspartimide formation during peptide synthesis using cyanosulfurylides as carboxylic acid-protecting groups. Nature Communications (2020).
4. Nanopore sensing reveals a preferential pathway for the co-translocational unfolding of a conjugative relaxase–DNA complex. Nucleic Acids Research (2023).
5. Chromatic Bacteria – A Broad Host-Range Plasmid and Chromosomal Insertion Toolbox for Fluorescent Protein Expression in Bacteria. Frontiers in Microbiology (2018).