A regenerating free-energy register for protein-templated period-2 DNA synthesis by Drt3b

Abstract

Deng et al. discovered that Drt3b synthesizes protein-primed poly(AC) DNA without a nucleic-acid template. The structures reveal a finite protein architecture and product-associated contacts, but not the renewable dynamical rule that converts a bounded pocket into a long period-2 sequence. We propose that Drt3b is a regenerating protein-substrate free-energy register. The framework specifies a sampled quantum mechanics/molecular mechanics (QM/MM) potential of mean force and a preregistered, within-domain first-order electronic-descriptor map for edge-specific activation barriers; physical curvature is admitted only through a training-frozen Taylor-remainder bound that widens uncertainty but never corrects a held-out mean. Conditional hazards derived from those barriers are averaged over unresolved conformational, hydration, protonation, and metal-coordination trajectories to yield a semi-Markov event kernel. Pointwise ratios of competing hazards are therefore fixed by the same barrier differences and preregistered prefactor rules that govern exit timing, so nucleotide choice and dwell statistics are co-generated rather than separately fitted. A regime gate separates stationary or slowly driven experiments, analyzed by a joint sequence-time cycle determinant, from genuinely nonstationary protocols, analyzed by the full age-structured tilted propagator. The decisive test is one locked parameterization: without condition-specific refitting, it must jointly predict nucleotide choice, waiting-time laws, product-length tails, and the rank, minors, null spaces, and rescue structure of perturbation responses. An independent 2026 DRT3 study supplies a stringent cross-construct transport test after sequence and structural alignment are frozen. The proposal requires neither coherent quantum computation nor coupling to an external field.