Microscopic Free-Energy Landscaping and Coarse-Grained 3D Dynamics of Scaffolded DNA Computers: Overcoming Kinetic Traps at Scale
Year: 2026
Type: preprint
Abstract: Thermodynamically favoured molecular computing encodes algorithmic solutions into ground-state equilibrium configurations of self-assembling DNA nanostructures, circumventing the dissipation bounds of non-equilibrium kinetic proofreading. However, practical scaling on biologically derived scaffolds (such as single-stranded M13 bacterio- phage DNA) has been severely constrained by heterogeneous base compositions that create energetic traps, kinetic stalls along long carry runs, and uncharacterized steric effects. Here, we present a multi-scale high-performance computational study uniting coarse-grained 3D molecular dynamics (oxDNA2), combinatorial Monte Carlo free- energy flattener algorithms, and continuous-time Gillespie kinetic Monte Carlo (KMC) simulations. From 3D trajectories of assembled 4-position complexes, we demonstrate that adjacent bound compute domains remain separated by an average physical distance of 18.43± 5.58 nm with zero direct contact probability, establishing that proofreading proceeds exclusively through solution-phase tile displacement rather than on-scaffold branch migration. By integrating the spatial probability density of the flexible single- stranded arms (RMSF = 10.14 nm), we extract an effective local concentration of Ceff = 63.37 µM, explaining a 63-fold kinetic acceleration that powers the directional assembly ratchet. We resolve the failure of naive global sequence flattening by discovering a hierarchical design window (∆G◦ scaffold ≈ −18.5 kcal/mol), which homogenizes scaffold duplex variances (σ = 0.61 kcal/mol) while preserving a critical 12.7 kcal/mol free-energy gap for error discrimination. Finally, across full 25-bit binary addition problems, we demonstrate that a non-linear dwell annealing schedule enables robust
Source: ChemRxiv
Author: Sharif Ahmad Naikoo
Institution: Indian Institute of Technology Kanpur
Language: English
Topic: DNA and Biological Computing
Subfield: Theoretical Computer Science
Field: Mathematics
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7223275722