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<p>Motor enzymes that interact with DNA are essential for replicative biological processes. In nanopore sequencing, a motor enzyme controls the motion of a nucleic acid through a protein nanopore, and sequence-dependent blockages of an ion current flowing through the nanopore are used to decode the DNA sequence. The kinetics of these enzymes are sequence-dependent and can serve as an additional source of information during sequencing. Here, we use Mutual Information (MI) to quantify the sequence-dependent kinetics of a Hel308 helicase during nanopore sequencing. We use MI to identify sites in Hel308 that are responsible for sequence-dependent kinetics and develop “k-mer” models of Hel308 kinetics that map kinetics to DNA sequence. We estimate that enzyme kinetics can improve nanopore sequencing accuracy by ~5-fold at high sequencing depth. We mutate Hel308 to identify amino acids involved in DNA translocation and suggest pathways for engineering molecular motors with enhanced responsiveness to DNA sequence.</p>

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An information theory approach to quantifying the sequence-dependent response of nucleic acid motors with applications to nanopore DNA sequencing

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月26日

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  • Jonathan M. Craig,
  • Andrew H. Laszlo,
  • Henry Brinkerhoff,
  • Christopher A. Thomas,
  • Sinduja K. Marx,
  • Eric F. Lebo,
  • Sarah J. Abell,
  • Michaela C. Franzi,
  • Jesse R. Huang,
  • Hwanhee C. Kim,
  • Jessica D. Carrasco,
  • Jens H. Gundlach

摘要

Motor enzymes that interact with DNA are essential for replicative biological processes. In nanopore sequencing, a motor enzyme controls the motion of a nucleic acid through a protein nanopore, and sequence-dependent blockages of an ion current flowing through the nanopore are used to decode the DNA sequence. The kinetics of these enzymes are sequence-dependent and can serve as an additional source of information during sequencing. Here, we use Mutual Information (MI) to quantify the sequence-dependent kinetics of a Hel308 helicase during nanopore sequencing. We use MI to identify sites in Hel308 that are responsible for sequence-dependent kinetics and develop “k-mer” models of Hel308 kinetics that map kinetics to DNA sequence. We estimate that enzyme kinetics can improve nanopore sequencing accuracy by ~5-fold at high sequencing depth. We mutate Hel308 to identify amino acids involved in DNA translocation and suggest pathways for engineering molecular motors with enhanced responsiveness to DNA sequence.