Evidence map›Paper›PMID 41712694›Full record

ArticleScience (New York, N.Y.)2026

Rapid directed evolution guided by protein language models and epistatic interactions.

Vincent Q Tran, Matthew Nemeth, Liam J Bartie, Sita S Chandrasekaran, Alison Fanton, Hyungseok C Moon, Brian L Hie, Silvana Konermann, Patrick D Hsu

Abstract read
In one paragraph

Article in Science (New York, N.Y.), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.

0numbers the graph read from it
0cells of the map it votes in
10citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

10 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
  4. Article
  5. Review
  6. Article
  7. Article
  8. Article
  9. Review
  10. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Vincent Q TranArc Institute, Palo Alto, CA, USA.ORCID 0009-0005-2705-5305
Matthew NemethArc Institute, Palo Alto, CA, USA.ORCID 0009-0001-1224-9116
Liam J BartieArc Institute, Palo Alto, CA, USA.
Sita S ChandrasekaranArc Institute, Palo Alto, CA, USA.
Alison FantonArc Institute, Palo Alto, CA, USA.ORCID 0000-0002-5404-1460
Hyungseok C MoonArc Institute, Palo Alto, CA, USA.ORCID 0000-0002-3291-4128
Brian L HieArc Institute, Palo Alto, CA, USA.ORCID 0000-0003-3224-8142
Silvana Konermann *Arc Institute, Palo Alto, CA, USA.ORCID 0000-0001-7915-1685
Patrick D Hsu *Arc Institute, Palo Alto, CA, USA.ORCID 0000-0002-9380-2648

Funding

Molecular tools for targeting RNAR01GM131073 · NIGMS · UNIVERSITY OF CALIFORNIA BERKELEY · PI HSU, PATRICK · 2019 to 2022
$1.3M
Mechanistic studies of RNA-targeting CRISPR systemsR01GM132465 · NIGMS · UNIVERSITY OF CALIFORNIA BERKELEY · PI HSU, PATRICK, LYUMKIS, DMITRY · 2020 to 2022
$908k
NIGMS NIH HHS R01 GM131073NIGMS NIH HHS R01 GM132465
6 · The paper itself

Abstract

Protein engineering is limited by the inefficient search through a high-dimensional sequence space to find combinations of synergistic mutations. Traditional approaches use stepwise mutation stacking, whereas machine learning methods require extensive datasets or multiple experimental rounds and are bottlenecked by costly, length-limited gene synthesis. We present MULTI-evolve (where MULTI stands for model-guided, universal, targeted installation of multimutants), a rapid evolution framework that systematically engineers multimutants. Our approach combines protein language models or existing functional data with epistatic modeling to predict synergistic combinations. Proposed multimutants are built through MULTI-assembly, a mutagenesis method enabling high-efficiency assembly across multikilobase sequences. Applying MULTI-evolve to three proteins achieved up to 10-fold improvements with a single round of machine learning-guided directed evolution. MULTI-evolve provides a streamlined approach for end-to-end, multimutant engineering for a broad range of protein types and functions.

Indexed as

Directed Molecular EvolutionEpistasis, GeneticProtein EngineeringProteinsMachine LearningMutagenesisMutationProteins

Identifiers

PMID41712694
PMCPMC12991030

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.