Hidden GPCR structural transitions addressed by multiple walker supervised molecular dynamics (mwSuMD).

Area of Science:

• Structural biology
• Computational biophysics
• Pharmacology

Background:

• G protein-coupled receptors (GPCRs) are crucial membrane proteins and drug targets, but their flexibility complicates structural studies.
• Understanding GPCR dynamics is key to developing new therapeutics, yet traditional methods face limitations.

Purpose of the Study:

• To introduce and validate a novel molecular dynamics (MD) adaptive sampling algorithm, multiple walker supervised molecular dynamics (mwSuMD).
• To simulate complex GPCR structural transitions and binding events without external energy input.

Main Methods:

• Developed and applied the multiple walker supervised molecular dynamics (mwSuMD) algorithm for adaptive sampling in molecular dynamics simulations.
• Simulated the binding and unbinding of vasopressin peptide from its V2 receptor.
• Simulated the complete transition of the glucagon-like peptide-1 receptor (GLP-1R) from inactive to active states, including Gs protein binding and GDP release.

Main Results:

• Successfully modeled the complete activation pathway of GLP-1R and associated Gs protein dynamics, including GDP release, without energy bias.
• Demonstrated the capability of mwSuMD to capture complex binding and unbinding events, such as vasopressin-V2 receptor interaction.
• Showcased mwSuMD's effectiveness in simulating protein dynamics previously inaccessible to classic MD methods.

Conclusions:

• The mwSuMD algorithm provides a powerful, unbiased approach for studying GPCR structural dynamics and functional transitions.
• This method enables in-depth investigation of the mechanisms underlying GPCR pharmacology and drug interactions.
• mwSuMD opens new avenues for understanding the complex dynamics of membrane proteins and their role in cellular signaling.