ArticlebioRxiv : the preprint server for biology2026
Mutation E300 recommended by protein language models gives ChrimsonR amplified photocurrent response.
Samuel Ehrlich, Alexandra D VandeLoo, Benjamin Magondu, Athena Chien, Sapna Sinha, Edward S Boyden, Craig R Forest
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In one paragraphArticle in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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5 · Who and what moneyAuthors and funding
7 authors.
Samuel EhrlichGeorge W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States.
Alexandra D VandeLooSchool of Materials Science and Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States.
Benjamin MagonduWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States.
Athena ChienWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States.
Sapna SinhaMcGovern Institute of Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States.
Edward S BoydenMcGovern Institute of Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States.
Craig R ForestGeorge W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States.
Funding
Novel Platforms for Systematic Optical Control of Complex Neural Circuits In VivoR01DA029639 · NIDA · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI BOYDEN, EDWARD S. · 2010 to 2023
$6.7MHigh-throughput robotic analysis of integrated neuronal phenotypesR01EY023173 · NEI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI BOYDEN, EDWARD S., FOREST, CRAIG · 2012 to 2016
$4.3MMultidimensional Optimization of Voltage Indicators for In Vivo Neural Activity ImagingR01MH122971 · NIMH · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · PI HAN, XUE · 2020 to 2024
$3.4MHigh throughput assaying of circuit activity and connectivity in brain organoidsRF1MH123977 · NIMH · HARVARD UNIVERSITY · PI ARLOTTA, PAOLA, BOYDEN, EDWARD S. · 2020 to 2020
$2.5MAutomated cell-type-specific electrophysiology for understanding circuit dysregulation in Alzheimer's DiseaseRF1AG079269 · NIA · EMORY UNIVERSITY · PI FOREST, CRAIG, ROWAN, MATTHEW J.M. · 2022 to 2024
$2.4MScalable Cell- and Circuit-Targeted ElectrophysiologyR01NS102727 · NINDS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI BOYDEN, EDWARD S., FOREST, CRAIG · 2017 to 2020
$2.2MIn-vivo circuit activity measurement at single cell, sub-threshold resolutionU01MH106027 · NIMH · GEORGIA INSTITUTE OF TECHNOLOGY · PI FOREST, CRAIG, STANLEY, GARRETT B. · 2014 to 2016
$1.5MNEI NIH HHS R01 EY023173NIA NIH HHS RF1 AG079269NIDA NIH HHS R01 DA029639NIMH NIH HHS R01 MH122971NIMH NIH HHS RF1 MH123977NIMH NIH HHS U01 MH106027NINDS NIH HHS R01 NS102727
6 · The paper itselfAbstract
A central challenge in opsin engineering is identifying mutations that reliably improve desired functional properties, a task made difficult by the enormous mutation space and limited throughput of electrophysiological screening. Improving opsin properties such as photocurrent amplitude and light sensitivity have the potential to broaden the use of opsins to low-light and deep-tissue applications. With this goal, we applied zero-shot protein language models (ESM-1b/1v) to recommend ChrimsonR mutations and experimentally validated all 17 of these variants using whole-cell patch clamp electrophysiology (n=6 cells per mutation). Despite many mutations reducing function, protein language models identified both known functional residues and unconventional substitutions that produced large functional gains and synergized with K176R to improve kinetics. Two mutations, E300G and E300P, increased sustained photocurrents from 66 pA (control) to 305 pA and 255 pA at 635 nm, reduced EC
Indexed as
ElectrophysiologyOpsin EngineeringPatch ClampProtein Language Modeling
Identifiers
PMID42182401
PMCPMC13192664
What OpenQuestion holds
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LicenceCC BY-NC
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