Dynamic mechanism for subtype selectivity of endocannabinoids.

Area of Science:

• Biophysics
• Computational Chemistry
• Pharmacology

Background:

• Endocannabinoids regulate bodily functions via the endocannabinoid system.
• Developing selective cannabinoid receptor (CB) drugs is a major interest.
• Biophysical mechanisms of endocannabinoid subtype selectivity remain unclear.

Purpose of the Study:

• To elucidate the biophysical mechanisms behind anandamide selectivity for the CB1 receptor.
• To test hypotheses involving enthalpic interactions and volumetric differences in binding pockets.
• To characterize the anandamide binding process using advanced computational methods.

Main Methods:

• Extensive molecular dynamics simulations (∼0.9 milliseconds).
• Markov state modeling and deep learning-based VAMPnets.
• Relative free energy calculations for anandamide analogs.

Main Results:

• Distinct N-terminus positions influence anandamide binding mechanisms and interactions.
• CB2 receptor's larger pocket volume increases entropic effects.
• CB1 selectivity is driven by dominant enthalpy contributions from ligand-protein interactions.

Conclusions:

• Opposing enthalpy and entropy effects shape endocannabinoid selectivity.
• Anandamide's CB1 selectivity is explained by favorable enthalpic interactions.
• Findings aid in the discovery of novel CB selective drugs.