Mechanistic origin of partial agonism of tetrahydrocannabinol for cannabinoid receptors

Dutta, Soumajit; Selvam, Balaji; Das, Aditi; Shukla, Diwakar

doi:10.1016/j.jbc.2022.101764

Cited by 22 publications

(21 citation statements)

References 81 publications

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“…To determine the error bars for the MFPTs and free energy of the MSM, 100 rounds of bootstrapping were performed for each simulated trajectory. − In each bootstrap sample, we randomly picked N trajectories (with replacement), where N is the number of total trajectories. We kept the state labeling as the original MSM but constructed a new MSM based on new sampled trajectories.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation Regulation Mechanism of β2 Integrin for the Binding of Filamin Revealed by Markov State Model

Hong

Song

Rahman

et al. 2023

J. Chem. Inf. Model.

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Leukocyte adhesion deficiency-1 (LAD-1) disorder is a severe immunodeficiency syndrome caused by deficiency or mutation of β2 integrin. The phosphorylation on threonine 758 of β2 integrin acts as a molecular switch inhibiting the binding of filamin. However, the switch mechanism of site-specific phosphorylation at the atom level is still poorly understood. To resolve the regulation mechanism, all-atom molecular dynamics simulation and Markov state model were used to study the dynamic regulation pathway of phosphorylation. Wild type system possessed lower binding free energy and fewer number of states than the phosphorylated system. Both systems underwent local disorder-to-order conformation conversion when achieving steady states. To reach steady states, wild type adopted less number of transition paths/shortest path according to the transition path theory than the phosphorylated system. The underlying phosphorylated regulation pathway was from P1 to P0 and then P4 state, and the main driving force should be hydrogen bond and hydrophobic interaction disturbing the secondary structure of phosphorylated states. These studies will shed light on the pathogenesis of LAD-1 disease and lay a foundation for drug development.

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Section: Methodsmentioning

confidence: 99%

Phosphorylation Regulation Mechanism of β2 Integrin for the Binding of Filamin Revealed by Markov State Model

Hong

Song

Rahman

et al. 2023

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…If the extent of reweighting between the raw and MSM-adjusted data deviates beyond a relationship of x = y where y is much greater than x , then the molecular descriptors used for MSM featurization are deriving an overtuned bias correction. 79,80 In this case, molecular descriptors that are highly correlated to tIC1 and tIC2 of the exhaustive tICA decomposition can be used to simplify the MSM featurization step. Repeat Steps 1-3 using molecular descriptor feature sets inspired from Step 4 until the raw cluster counts versus MSM-reweighting plots approximately satisfy a relationship of x=y.…”

Section: Methodsmentioning

confidence: 99%

AtSWEET13 transporter discriminates sugars by selective facial and positional substrate recognition

Weigle

Shukla

2022

Preprint

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Transporters are targeted by endogenous metabolites and exogenous molecules to reach cellular destinations, but it is generally not understood how different substrate classes exploit the same transporter's mechanism. Any disclosure of plasticity in transporter mechanism when treated with different substrates becomes critical for developing general selectivity principles in membrane transport catalysis. Using extensive molecular dynamics simulations with an enhanced sampling approach, we select the Arabidopsis sugar transporter AtSWEET13 as a model system to identify the basis for glucose versus sucrose molecular recognition and transport. We find that AtSWEET13 chemical selectivity originates from a conserved substrate facial selectivity demonstrated when committing alternate access, despite mono-/di-saccharides experiencing differing degrees of conformational and positional freedom throughout other stages of transport. In summary, our results point to a potentially generalizable finding that selectivity in transporters emerges from molecular recognition events occurring within regions distal from any conserved (non)functional binding sites.

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“…67 Thus, to capture the entire protein conformational ensemble, adaptive sampling protocol was implemented. [67][68][69][70] Adaptive sampling is a well established sampling technique used for studying ligand binding, [71][72][73] protein conformational change 63,[74][75][76] and ligand selectivity. 77 S7 and S8).…”

Section: Adaptive Samplingmentioning

confidence: 99%

Distinct Activation Mechanisms Regulate Subtype Selectivity of Cannabinoid Receptors

Dutta

Shukla

2022

Preprint

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Cannabinoid receptors (CB1 and CB2) are important drug targets for inflammation, obesity, and other central nervous system disorders. However, due to sequence and structural similarities of the ligand binding pockets of these receptors, most of the ligands lack subtype selectivity and cause off-target side effects. CB2 selective agonists can potentially treat pain and inflammation without the psychoactive effects of CB1 agonism. We hypothesize that the subtype selectivity of designed selective ligands can be explained by ligand binding to the conformationally distinct states between CB1 and CB2. To find these conformationally distinct states, we perform 700 μs of unbiased simulations to study the activation mechanism of both the receptors in absence of ligands. The simulation datasets of two receptors were analyzed using Markov state models to identify similarities and distinctions of the major conformational changes associated with activation and allosteric communication between them. Specifically, toggle switch residue movement and its effect on receptor activation differ greatly between CB1 and CB2. Upon further analysis, we discretize the conformational ensembles of both receptors into metastable states using the neural network-based VAMPnets. Structural and dynamic comparisons of these metastable states allow us to decipher a coarse-grained view of protein activation by revealing sequential conversion between these states. Specifically, we observe the difference in the binding pocket volume of different metastable states of CB1, whereas there are minimal changes observed in the CB2. Docking analysis reveals that differential binding pocket volume leads to distinct binding poses and docking affinities of CB2 selective agonists in CB1. Only a few of the intermediate metastable states of CB1 shows high affinity towards CB2 selective agonists. On the other hand, all the CB2 metastable states show a similar affinity for CB2 selective agonists, explaining these ligands overall higher affinity towards CB2. Overall, this computational study mechanistically explains the subtype selectivity of CB2 selective ligands by deciphering the activation mechanism of cannabinoid receptors.

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Mechanistic origin of partial agonism of tetrahydrocannabinol for cannabinoid receptors

Cited by 22 publications

References 81 publications

Phosphorylation Regulation Mechanism of β2 Integrin for the Binding of Filamin Revealed by Markov State Model

Phosphorylation Regulation Mechanism of β2 Integrin for the Binding of Filamin Revealed by Markov State Model

AtSWEET13 transporter discriminates sugars by selective facial and positional substrate recognition

Distinct Activation Mechanisms Regulate Subtype Selectivity of Cannabinoid Receptors

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