oligonucleotides

name	oligonucleotides
description	Design small interfering RNA and antisense oligonucleotide sequences against a transcript, and screen them for the failure modes specific to nucleic-acid drugs. Use this skill to tile a target transcript, apply positional and thermodynamic selection rules including duplex asymmetry and nearest-neighbour melting temperature, scan candidates for seed-region complementarity to off-target transcripts, and lay out a chemical modification pattern — gapmer architecture, 2'-O-methyl and 2'-MOE wings, locked nucleic acid, and phosphorothioate placement. Also trigger on siRNA, antisense oligonucleotide, ASO, gapmer, RNase H, seed region, duplex asymmetry, 2'-MOE, locked nucleic acid, phosphorothioate, or GalNAc conjugate.
license	MIT
allowed-tools	Read Write Edit Bash
compatibility	Requires Python 3.10+ only. Sequence tiling, nearest-neighbour thermodynamics, and seed-match scanning are implemented in the standard library, so there is no install and no network access. Transcriptome-wide off-target scanning needs a local FASTA file that you supply; no reference sequence is bundled.
metadata	{"version":"1.0","skill-author":"K-Dense Inc.","openclaw":{"emoji":"🧵","homepage":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822268/"},"hermes":{"category":"research"}}

Oligonucleotide Therapeutics

The modality that sidesteps the protein entirely. If a target has no druggable pocket, no extracellular epitope, and no ligandable cysteine, an siRNA or antisense oligonucleotide can still silence its transcript — and the design is sequence arithmetic rather than chemistry intuition.

No installation, no network, no key. Sequence tiling, nearest-neighbour thermodynamics, and seed scanning are implemented in the standard library. Transcriptome-wide off-target scanning needs a FASTA that you supply. Thermodynamics: SantaLucia (1998) unified nearest-neighbour parameters.

Read references/sirna-and-aso-design.md before choosing a site, references/chemical-modifications.md before drawing a pattern, and references/delivery-and-safety.md before committing to the modality — that one is judgement, not syntax, and it is where programmes fail.

The three scripts

Script	Answers
oligo_design.py	Which sites, and are their thermodynamics right?
offtarget_scan.py	What else will this silence?
chemistry_plan.py	What modifications, and where?

Two mechanisms, two incompatible rule sets

siRNA loads into Argonaute-2 and is cleaved by RISC in the cytoplasm — it needs an RNA-like duplex throughout. Gapmer ASO recruits RNase H1, works in the nucleus, and needs an unmodified DNA core.

Two consequences. ASOs can target introns and pre-mRNA; siRNA cannot, because RISC only sees mature mRNA. And the chemistry is not interchangeable: a DNA gap in an siRNA breaks Argonaute loading, while fully modifying an ASO silently removes RNase H recruitment — the molecule binds its target beautifully and does nothing.

Duplex asymmetry decides which strand is loaded

The siRNA rule that matters most. RISC keeps the strand whose 5' end is less thermodynamically stable. Get it backwards and RISC loads the sense strand, silences something else, and your molecule looks simply inactive — sending you to hunt for delivery problems that do not exist.

python skills/oligonucleotides/scripts/oligo_design.py tile --sequence ACGT... --modality sirna