A Multiscale Simulation Framework for Elucidating Photochemical Structure-Activity Relationships of Photoswitchable...

Area of Science:

• Computational chemistry
• Biophysics
• Pharmacology

Background:

• Predicting photochemical structure-activity relationships (photo-SAR) for photoswitchable ligands is challenging due to complex biomolecular interactions and dynamics.
• Existing methods struggle to accurately model protein-ligand interactions, electron correlation, and coupled nuclear/electronic dynamics.

Purpose of the Study:

• Develop a unified multiscale simulation framework to predict photo-SAR in complex biological environments.
• Investigate the photodynamics and binding affinities of photostatins (PSTs), light-regulated anticancer agents.
• Provide mechanistic insights for rational design of photoswitchable ligands.

Main Methods:

• Integrated first-principles nonadiabatic dynamics, excited-state enhanced sampling, and ground-state alchemical free-energy calculations.
• Applied the framework to photostatins (PSTs) and validated against experimental data (crystallography, spectra, bioassays).
• Compared thermodynamic integration with other free-energy methods for accuracy.

Main Results:

• Nonradiative decay rates correlate with excited-state free-energy surfaces, influenced by substituents, protein electrostatics, and steric confinement.
• Protein electrostatics accelerate relaxation, while steric constraints hinder it, determining PST derivative photodynamics.
• Photoisomerization quantum yield depends on torsional motion alignment and ground-state isomerization propensity, both shaped by protein-ligand interactions.
• Thermodynamic integration best captured substituent effects on binding affinity differences between isomers.

Conclusions:

• The developed framework accurately predicts photodynamics and light-responsive binding affinities of photoswitchable ligands.
• Protein electrostatics and steric factors critically modulate excited-state dynamics and photoisomerization quantum yield.
• This approach facilitates the rational design of photoswitchable ligands for biological and biomedical applications.