RISC Slicer — RNA Interference Mechanism

RNAi Pathway Controls

Active RISC (siRNA-AGO2) complexes 14

Transcription rate (new mRNA/s) 2.0

Seed-pairing mismatch tolerance 1

Cytoplasmic thermal motion 1.0×

Live Readouts

Target mRNA present

Gene knockdown

Cleavage events (total)

Cleavage rate

0.0 /s

How it works

RNA interference (RNAi) silences a gene post-transcriptionally. Dicer cleaves long double-stranded RNA into ~21–23 nt small interfering RNA (siRNA) duplexes; the guide strand is loaded into Argonaute2 (AGO2) to form the RNA-Induced Silencing Complex (RISC). RISC then scans diffusing mRNA transcripts for complementarity.

Targeting is dominated by the seed region (guide nucleotides 2–8): near-perfect seed pairing is required for stable engagement, while mismatches elsewhere are more tolerated (Bartel, 2009). This sim models each mRNA's complementarity as a mismatch count m and gives every RISC–mRNA encounter a binding probability

P_bind = 1 / (1 + exp[(m − tolerance) · s])

a logistic cutoff around the mismatch-tolerance slider (steepness s), capturing how sharply seed mismatches destroy affinity. A successful bind is followed by a fixed conformational + catalytic dwell (~0.9 s) before AGO2's RNase-H-like slicer domain cuts the phosphodiester backbone opposite guide positions 10–11 — visualized here as the transcript splitting into two fragments that drift apart and are degraded by exonucleases. Because AGO2 is not consumed by the reaction, the freed RISC immediately continues to survey new transcripts (multiple-turnover catalysis, unlike single-turnover antisense oligonucleotides).

Population dynamics follow a birth–death balance between ongoing transcription and RNAi-driven decay:

dM/dt = k_tx − k_nat·M − k_RISC·[RISC_free]·M
M_steady ≈ k_tx / (k_nat + k_RISC·[RISC_free])

Raise the mismatch tolerance to loosen seed specificity (faster, less discriminate silencing — more like an off-target effect); raise transcription rate to fight the knockdown with fresh mRNA supply; add more RISC complexes to model higher siRNA dose.

Target mRNA RISC (siRNA·AGO2) Cleaved fragment

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RISC Slicer — RNA Interference Gene Silencing