Protein folding remains a formidable challenge despite significant advances, particularly in sequence-to-structure prediction. Accurately capturing thermodynamics and intermediates via simulations dem...

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 framework, we mapped the multidimensional free energy landscapes of the ADRB1 receptor in both its apo- and adrenaline-bound holo states. Our analysis reveals a detailed, stepwise activation pathway that quantifies the known modulatory roles of sodium ions and protonation states and identifies essential water-mediated networks that stabilize the active conformation. This work provides a detailed overview of ADRB1 activation and establishes the robustness of our OneOPES approach for investigating complex activation mechanisms with the potential for application to other Class A GPCRs.

Biology is hard. Yes, even for AI.

International students contributed $43.8bn to the US economy last year and created 378,175 jobs nationwide.

A force field as accurate as quantum mechanics (QMs) and as fast as molecular mechanics (MMs), with which one can simulate a biomolecular system efficiently eno

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Since US President Donald Trump took office in January 2025, his team has made major changes to the federal government that have disrupted research and ...

G protein-coupled receptors (GPCRs) are critical drug targets involved in numerous physiological processes, yet many of their structures remain unresolved due to inherent flexibility and diverse ligan...

In computational physics, chemistry, and biology, the implementation of new techniques in a shared and open source software lowers barriers to entry and promotes rapid scientific progress. However, ef...

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