Free-energy simulations reveal molecular mechanism for functional switch of a DNA helicase

Ma, Wen; Whitley, Kevin D.; Chemla, Yann R.; Luthey‐Schulten, Zaida; Schulten, Klaus

doi:10.7554/elife.34186

“…With the methods used in this investigation, a similar ramp in fungal ORFeomes was not identified. From a resource allocation perspective, a ramp of hydrogen bonding found in Bacteria and Archaea may provide an energy-efficient mechanism in which the energy required to melt hydrogen bonds ( 38 – 40 ) and unwind dsDNA is gradually increased. It has been reported previously that AU-rich codons are selected for at the beginning of CDSs in E. coli and other organisms ( 35 ) and that genomic GC content shows positional dependency in diverse organisms ( 41 ), which would in turn reduce the local hydrogen bonding at the 5ʹ end of CDSs.…”

Section: Discussionmentioning

confidence: 99%

Interplay between Position-Dependent Codon Usage Bias and Hydrogen Bonding at the 5ʹ End of ORFeomes

Villada

¹

,

Duran

²

,

Lee

³

2020

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Codon usage bias exerts control over a wide variety of molecular processes. The positioning of synonymous codons within coding sequences (CDSs) dictates protein expression by mechanisms such as local translation efficiency, mRNA Gibbs free energy, and protein cotranslational folding. In this work, we explore how codon usage affects the position-dependent content of hydrogen bonding, which in turn influences energy requirements for unwinding double-stranded DNA (dsDNA). We categorized codons according to their hydrogen bond content and found differential effects on hydrogen bonding encoded by codon variants. The specific positional disposition of codon variants within CDSs creates a ramp of hydrogen bonding at the 5ʹ end of the ORFeome in Escherichia coli. CDSs occupying the first position of operons are subjected to selective pressure that reduces their hydrogen bonding compared to internal CDSs, and highly transcribed CDSs demand a lower maximum capacity of hydrogen bonds per codon, suggesting that the energetic requirement for unwinding the dsDNA in highly transcribed CDSs has evolved to be minimized in E. coli. Subsequent analysis of over 14,000 ORFeomes showed a pervasive ramp of hydrogen bonding at the 5ʹ end in Bacteria and Archaea that positively correlates with the probability of mRNA secondary structure formation. Both the ramp and the correlation were not found in Fungi. The position-dependent hydrogen bonding might be part of the mechanism that contributes to the coordination between transcription and translation in Bacteria and Archaea. A Web-based application to analyze the position-dependent hydrogen bonding of ORFeomes has been developed and is publicly available (https://juanvillada.shinyapps.io/hbonds/). IMPORTANCE Redundancy of the genetic code creates a vast space of alternatives to encode a protein. Synonymous codons exert control over a variety of molecular and physiological processes of cells mainly through influencing protein biosynthesis. Recent findings have shown that synonymous codon choice affects transcription by controlling mRNA abundance, mRNA stability, transcription termination, and transcript biosynthesis cost. In this work, by analyzing thousands of Bacteria, Archaea, and Fungi genomes, we extend recent findings by showing that synonymous codon choice, corresponding to the number of hydrogen bonds in a codon, can also have an effect on the energetic requirements for unwinding double-stranded DNA in a position-dependent fashion. This report offers new perspectives on the mechanism behind the transcription-translation coordination and complements previous hypotheses on the resource allocation strategies used by Bacteria and Archaea to manage energy efficiency in gene expression.

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“…With the methods used in this investigation, a similar ramp in fungal ORFeomes was not identified. From a resource allocation perspective, a ramp of hydrogen bonding found in prokaryotes may provide an energy-efficient mechanism to unwind dsDNA and facilitate transcript elongation by reducing the local energy required to melt hydrogen bonds [30][31][32] . It has been reported previously that AU-rich codons are selected for at the beginning of CDSs in E. coli 33 , which would in turn reduce the local hydrogen bonding at the 5 -end of CDSs.…”

Section: Discussionmentioning

confidence: 99%

Codon usage bias creates a ramp of hydrogen bonding at the 5′-end in prokaryotic ORFeomes

Villada

¹

,

Duran

²

,

Lee

³

2019

Preprint

0

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Codon usage bias exerts control over a wide variety of molecular processes. The positioning of synonymous codons within coding sequences (CDSs) dictates protein expression by mechanisms such as local translation efficiency, mRNA Gibbs free energy, and protein co-translational folding. In this work, we explore how codon variants affect the position-dependent content of hydrogen bonding, which in turn influences energy requirements for unwinding double-stranded DNA. By analyzing over 14,000 bacterial, archaeal, and fungal ORFeomes, we found that Bacteria and Archaea exhibit an exponential ramp of hydrogen bonding at the 5 -end of CDSs, while a similar ramp was not found in Fungi. The ramp develops within the first 20 codon positions in prokaryotes, eventually reaching a steady carrying capacity of hydrogen bonding that does not differ from Fungi. Selection against uniformity tests proved that selection acts against synonymous codons with high content of hydrogen bonding at the 5 -end of prokaryotic ORFeomes. Overall, this study provides novel insights into the molecular feature of hydrogen bonding that is governed by the genetic code at the 5 -end of CDSs. A web-based application to analyze the position-dependent hydrogen bonding of ORFeomes has been developed and is publicly available (https: //juanvillada.shinyapps.io/hbonds/).

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“…[]. Umbrella sampling is perhaps the most widely used approached to compute the free energy of a biomolecular system along a well‐defined reaction coordinate and is especially applicable to the study of DNA–protein conformations …”

Section: Methodsmentioning

confidence: 99%

Molecular Mechanisms of DNA Replication and Repair Machinery: Insights from Microscopic Simulations

Chou

¹

,

Aksimentiev

²

2019

Advcd Theory and Sims

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Reproduction, the hallmark of biological activity, requires making an accurate copy of the genetic material to allow the progeny to inherit parental traits. In all living cells, the process of DNA replication is carried out by a concerted action of multiple protein species forming a loose protein-nucleic acid complex, the replisome. Proofreading and error correction generally accompany replication but also occur independently, safeguarding genetic information through all phases of the cell cycle. Advances in biochemical characterization of intracellular processes, proteomics, and the advent of single-molecule biophysics have brought about a treasure trove of information awaiting to be assembled into an accurate mechanistic model of the DNA replication process. This review describes recent efforts to model elements of DNA replication and repair processes using computer simulations, an approach that has gained immense popularity in many areas of molecular biophysics but has yet to become mainstream in the DNA metabolism community. It highlights the use of diverse computational methods to address specific problems of the fields and discusses unexplored possibilities that lie ahead for the computational approaches in these areas.

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Free-energy simulations reveal molecular mechanism for functional switch of a DNA helicase

Cited by 17 publications

References 76 publications

Interplay between Position-Dependent Codon Usage Bias and Hydrogen Bonding at the 5ʹ End of ORFeomes

Interplay between Position-Dependent Codon Usage Bias and Hydrogen Bonding at the 5ʹ End of ORFeomes

Codon usage bias creates a ramp of hydrogen bonding at the 5′-end in prokaryotic ORFeomes

Molecular Mechanisms of DNA Replication and Repair Machinery: Insights from Microscopic Simulations

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