Microscopic Free-Energy Landscaping and Coarse-Grained 3D Dynamics of Scaffolded DNA Computers: Overcoming Kinetic Traps at Scale
- 1Department of Chemistry
- 2Indian Institute of Technology Kanpur
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
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BibTeX
@misc{naikoo2026microscopic,
title = {{Microscopic Free-Energy Landscaping and Coarse-Grained 3D Dynamics of Scaffolded DNA Computers: Overcoming Kinetic Traps at Scale}},
author = {Sharif Ahmad Naikoo},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010917/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010917/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Microscopic Free-Energy Landscaping and Coarse-Grained 3D Dynamics of Scaffolded DNA Computers: Overcoming Kinetic Traps at Scale
AU - Sharif Ahmad Naikoo
PY - 2026
DA - 2026/10/22
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010917/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010917/v1
AB - 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
ER -