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This study introduces a novel method combining in vitro selection and machine learning to discover functional biopolymers. The approach generates diverse, high-affinity nucleic acid polymers unrelated to initial discoveries, accelerating biopolymer engineering.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Chemistry

Background:

  • In vitro selection is crucial for discovering functional polymers from vast sequence spaces.
  • Exploring novel sequence space beyond experimental variants is challenging.
  • Limitations in selection and sequencing restrict the discovery of diverse functional biopolymers.

Purpose of the Study:

  • To develop an integrated approach combining in vitro selection and machine learning.
  • To discover novel highly side-chain-functionalized nucleic acid polymers (HFNAPs) with high affinity for daunomycin.
  • To generate diverse HFNAP sequences unrelated to experimentally derived variants using machine learning.

Main Methods:

  • In vitro selection was used to identify HFNAPs with daunomycin binding activity.
  • A conditional variational autoencoder (CVAE) machine learning model was trained on selection data.
  • The CVAE model generated novel HFNAP sequences with predicted high daunomycin affinities.

Main Results:

  • HFNAPs with potent daunomycin affinities (KD = 5-65 nM) were discovered.
  • The CVAE model generated diverse HFNAP sequences with improved daunomycin affinities (KD = 9-26 nM).
  • Generated sequences were unrelated to those obtained through experimental selection, expanding sequence space exploration.

Conclusions:

  • Coupling in vitro selection with machine learning enables efficient discovery of functional biopolymers.
  • This integrated approach allows for the direct generation of active variants beyond experimental limitations.
  • Demonstrates a powerful new strategy for biopolymer engineering and functional discovery.