Enhanced Sampling and Tailored Collective Variables Yield Reproducible Free Energy Landscapes of Beta-1 Adrenergic...

Area of Science:

• Biochemistry and biophysics
• Computational chemistry
• Pharmacology

Background:

• The beta-1 adrenergic receptor (ADRB1) is a key target for cardiovascular therapies.
• Understanding ADRB1 activation mechanisms is crucial but challenging for conventional simulation methods.
• The complex interplay of agonists, ions, water, and protein microswitches requires advanced computational approaches.

Purpose of the Study:

• To elucidate the detailed activation pathway of the beta-1 adrenergic receptor (ADRB1).
• To investigate the roles of sodium ions, protonation states, and water molecules in ADRB1 activation.
• To establish a novel enhanced sampling framework for studying GPCR activation.

Main Methods:

• Implementation of a OnePES enhanced sampling framework.
• Integration with biologically motivated collective variables (CVs) to track microswitches, ion binding, and water dynamics.
• Mapping multidimensional free energy landscapes for apo- and holo-ADRB1 states.

Main Results:

• Detailed, stepwise activation pathway of ADRB1 revealed.
• Quantified modulatory roles of sodium ions and protonation states.
• Identified essential water-mediated networks stabilizing the active receptor conformation.
• Demonstrated the robustness of the OnePES approach for complex activation mechanisms.

Conclusions:

• The study provides a comprehensive overview of ADRB1 activation.
• The developed OnePES framework is effective for investigating complex biological systems.
• This approach has potential applications for studying other Class A G protein-coupled receptors (GPCRs).