Abstract
Since the elucidation of the genetic code almost 50 years ago, many nonrandom aspects of its codon organization remain only partly resolved. Here, we investigate the recent hypothesis of ‘dual-use’ codons which proposes that in addition to allowing adjustment of codon optimization to tRNA abundance, the degeneracy in the triplet-based genetic code also multiplexes information regarding DNA’s helical shape and protein-binding dynamics while avoiding interference with other protein-level characteristics determined by amino acid properties. How such structural optimization of the code within eukaryotic chromatin could have arisen from an RNA world is a mystery, but would imply some preadaptation in an RNA context. We analyzed synonymous (protein-silent) and nonsynonymous (protein-altering) mutational impacts on molecular dynamics in 13823 identically degenerate alternative codon reorganizations, defined by codon transitions in 7680 GPU-accelerated molecular dynamic simulations of implicitly and explicitly solvated double-stranded aRNA and bDNA structures. When compared to all possible alternative codon assignments, the standard genetic code minimized the impact of synonymous mutations on the random atomic fluctuations and correlations of carbon backbone vector trajectories while facilitating the specific movements that contribute to DNA polymer flexibility. This trend was notably stronger in the context of RNA supporting the idea that dual-use codon optimization and informational multiplexing in DNA resulted from the preadaptation of the RNA duplex to resist changes to thermostability. The nonrandom and divergent molecular dynamics of synonymous mutations also imply that the triplet-based code may have resulted from adaptive functional expansion enabling a primordial doublet code to multiplex gene regulatory information via the shape and charge of the minor groove.
Highlights
All known life on Earth uses nearly the same genetic code to control the templated reproduction of polypeptides from nucleic acid polymers
Table shows the empirical p value for the genetic code’s biophysically defined mutational impacts for dTRX when compared to all possible codon reassignments with similar levels of degeneracy nonsynonymous or synonymous on both leading and lagging strands when reading in a 5′–3′ direction (i.e., N–N or S–S) or whether it is synonymous on one side but not the other (i.e., S–N)], we find that the trend of minimized impacts of synonymous mutation is much greater when the context is asymmetrical (Fig. 3; Tables 1, 2)
This general trend of minimization of mutational impact on overall backbone dynamics of synonymous sites is accompanied by optimization that maximizes particular movements that facilitate DNA flexibility
Summary
All known life on Earth uses nearly the same genetic code to control the templated reproduction of polypeptides from nucleic acid polymers. Its triplet-based codon organization appears to serve two rather distinct functions. A less obvious secondary function is the accommodation of nucleic acid sequence level variation for reasons that are still largely unknown. This degeneracy in the code is achieved through the prevalence of twofold and fourfold synonymous sites which occur mostly at the third codon position and are frequently accommodated by nonspecific base pairing and tRNA wobble at the ribosome (Crick 1966). The triplet codon would appear to allow these
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