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

ABSTRACT: The beta-1 adrenergic receptor (ADRB1) is a critical target for cardiovascular drugs, yet our understanding of how it is activated remains incomplete. Capturing the concerted interplay of agonists, solvent, ions, and protein microswitches is a significant challenge for conventional simulation methods and is essential for unraveling this process. Here, we address this challenge by implementing a powerful enhanced sampling framework that integrates the OneOPES enhanced sampling algorithm with a set of biologically motivated collective variables (CVs). These CVs are designed to track several key features of the activation process simultaneously, including rearrangement of conserved microswitches, the state of the sodium ion binding pocket, and dynamics of critical water molecules. Using this

SUBMITTER: Aureli S 

PROVIDER: S-EPMC12355687 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature