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Related Experiment Video

Updated: Jun 5, 2026

Proton Transfer and Protein Conformation Dynamics in Photosensitive Proteins by Time-resolved Step-scan Fourier-transform Infrared Spectroscopy
10:03

Proton Transfer and Protein Conformation Dynamics in Photosensitive Proteins by Time-resolved Step-scan Fourier-transform Infrared Spectroscopy

Published on: June 27, 2014

Multiscale Free-Energy Methods for Protonation-Coupled Light-Responsive Binding of Ionizable Photoswitchable eDHFR

Mohammad Khavani, Kambham Devendra Reddy, Pauf Neupane

    Biorxiv : the Preprint Server for Biology
    |June 4, 2026
    PubMed
    Summary

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    A Multiscale Simulation Framework for Elucidating Photochemical Structure-Activity Relationships of Photoswitchable Ligands in Complex Biomolecular Environments.

    Journal of chemical information and modeling·2025

    A new computational method accurately predicts how photoswitchable ligands bind to targets, crucial for designing new light-controlled drugs. This method accounts for protonation changes, improving photopharmacology applications.

    Area of Science:

    • Computational Chemistry
    • Photopharmacology
    • Biomolecular Interactions

    Background:

    • Photoswitchable ligands offer light control over biomolecular activity.
    • Ionizable photoswitchable ligands present design challenges due to coupled effects on binding, isomerism, and protonation.
    • Predicting these effects computationally remains difficult.

    Purpose of the Study:

    • To establish and benchmark a multiscale free-energy method for predicting light-responsive binding of ionizable photoswitchable ligands.
    • To quantitatively characterize ligand protonation changes upon binding to dihydrofolate reductase (eDHFR).
    • To evaluate different computational approaches for predicting affinity changes and substituent effects.

    Main Methods:

    • Multiscale free-energy calculations combining constant pH replica-exchange molecular dynamics and QM/MM umbrella sampling.

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    Related Experiment Videos

    Last Updated: Jun 5, 2026

    Proton Transfer and Protein Conformation Dynamics in Photosensitive Proteins by Time-resolved Step-scan Fourier-transform Infrared Spectroscopy
    10:03

    Proton Transfer and Protein Conformation Dynamics in Photosensitive Proteins by Time-resolved Step-scan Fourier-transform Infrared Spectroscopy

    Published on: June 27, 2014

    Design, Synthesis, and Photochemical Properties of Clickable Caged Compounds
    09:44

    Design, Synthesis, and Photochemical Properties of Clickable Caged Compounds

    Published on: October 15, 2019

    Determination of the Photoisomerization Quantum Yield of a Hydrazone Photoswitch
    09:33

    Determination of the Photoisomerization Quantum Yield of a Hydrazone Photoswitch

    Published on: February 7, 2022

  • Thermodynamic integration simulations with various alchemical pathways and protonation state treatments.
  • Benchmarking against experimental data for photoswitchable eDHFR inhibitors.

    • Main Results:

    • The developed method accurately reproduces experimental trends in light-responsive binding affinity.
    • Explicit treatment of environment-dependent protonation states during isomer transformation is key for accuracy.
    • Ignoring binding-induced protonation changes leads to inconsistent predictions.

    Conclusions:

    • A systematic free-energy method is established for designing ionizable photoswitches.
    • Understanding protonation equilibria is critical for accurate prediction of photopharmacological responses.
    • This work advances computational design strategies in photopharmacology.