CB1R–THC | Membrane-system preparation and preliminary analysis

PAGE SCOPE

Objective, available data, and analysis limits

This page documents receptor and THC preparation, membrane-system construction, and analysis of the 300–400 ps window. Each stage identifies the available files and the limits of any conclusions.

Quick guide · Core concept

What is Molecular Docking and how is it applied here?

Direct concept: Molecular docking is an in silico computational method that generates candidate ligand orientations and conformations — called poses — in a protein region. A scoring function ranks these hypotheses; the resulting value is not an experimental affinity measurement.

Docking vs. molecular dynamics: docking proposes starting poses ranked by the protocol. Molecular dynamics calculates a model trajectory over successive time steps under defined conditions and parameters. The trajectory is not an experimental movie and does not automatically validate the starting pose.

01

Factors that influence the CB1R response

Receptor response depends on ligand, conformational state, cellular context, and experimental design.

02

Experimental structure and modeled pose

Follow how an experimental structure and a THC pose become a computational system that can be inspected over time.

03

Separation of results and hypotheses

Distinguish visualization, simulation-derived observables, experimental evidence, and biological inference before drawing conclusions.

SYSTEM CONTEXT

System composition and preparation

The receptor was prepared from PDB 5XRA, whose structure contains AM11542. THC was inserted separately by docking. The resulting trajectory represents a computational model of the system, not an experimental observation of CB1R–THC binding.

01

Receptor

5XRA-derived CB1R preparation, cleaned and used as a rigid docking receptor.

RCSB structural record ↗

02

Ligand

THC, PubChem CID 16078, prepared locally with a GAFF2-compatible parameter set.

Formula: C₂₁H₃₀O₂
Molar mass: 314.46 g·mol⁻¹
Local model: 53 atoms · 55 bonds

PubChem compound record ↗

03

Environment

POPC/CHL1 bilayer, TIP3P water, ff19SB protein, Lipid21 membrane, and GAFF2 ligand parameters.

04

Question

How do receptor shape, ligand contacts, and the membrane environment change across a simulated trajectory?

FUNCTIONAL PHARMACOLOGY

THC is commonly classified as a partial agonist at CB1R

In a given functional assay, a partial agonist activates the receptor but produces a lower maximal response than a high-efficacy full agonist used for comparison. This does not mean that THC only occupies part of the receptor or necessarily binds weakly. Apparent efficacy can vary with the measured signaling pathway, receptor density and reserve, cell or tissue context, assay conditions, and comparator.

That classification comes from functional pharmacology. A docking pose or a short molecular-dynamics trajectory cannot establish agonism, maximal efficacy, signaling bias, or a physiological response.

Evidence context: IUPHAR/BPS Guide to Pharmacology · functional CB1R study.

STUDY STATUS

Completed, under review, and planned stages

The four milestones distinguish documented material, the record under review, and the work still required to validate the trajectory.

0.1
Preparation and docking
Docking, ligand parameters, membrane construction, diagnostics, minimization, and heating.

Documented
0.2
Restricted equilibration and review
Outputs through the 300–400 ps analysis window, quality controls, and molecular visualizations.

Current record
0.3
Production dynamics
Longer sampling, independent replicas, and consolidated trajectory processing.

Planned
1.0
Technical report
Reproducible scripts, complete provenance, and conclusions bounded by the evidence.

Planned

What does molecular dynamics actually simulate?

A molecular-dynamics trajectory numerically propagates atomic positions and velocities under a selected force field. It can reveal relaxation, fluctuations, contacts, and environmental response within the model.

It does not automatically establish experimental affinity, physiological efficacy, or convergence. Those claims require validated preparation, adequate sampling, controls, and independent replicas.

How were the visual selections made in PyMOL?

SELECT RECEPTOR, CB1R_THC AND POLYMER.PROTEIN
SELECT THC, CB1R_THC AND RESN THC
SELECT MEMBRANE, CB1R_THC AND RESN PA+PC+OL+CHL

The visual convention uses cyan/teal for CB1R; green carbon, red oxygen, and white hydrogen atoms for THC; and yellow for the membrane. Use the animation to locate the receptor, THC, and membrane in the model. Evaluate stability using the documented trajectory metrics.

MOLECULAR VISUALIZATION

Visualizations of the CB1R–THC complex in a membrane

The gallery identifies the receptor, THC, the bilayer, and the orthosteric pocket. The animations show the recorded trajectory segment; stability and convergence must be assessed from metrics.

CB1R in cyan with THC highlighted in green at the orthosteric site, surrounded by a yellow membrane representation — **Modeled system composition**CB1R in cyan, THC in green, and the lipid bilayer in yellow; the image does not measure stability or affinity.

READING THE IMAGE

Membrane, receptor, and ligand in the image

The membrane appears as a yellow molecular network; CB1R is rendered in cyan/teal, and THC is highlighted with green carbon, red oxygen, and white hydrogen atoms at the orthosteric site. The image identifies components and spatial orientation but does not demonstrate trajectory convergence.

Membrane · yellowCB1R · cyan/tealTHC · green carbon + red oxygen

Close PyMOL view of green THC inside the CB1R orthosteric binding pocket, among cyan receptor helices — **THC in the orthosteric pocket**Modeled ligand position in the CB1R cavity

Isolated cyan ribbon representation of CB1R — **CB1R**Receptor representation

Isolated ball-and-stick representation of THC with green carbon, red oxygen, and white hydrogen atoms — **THC**Isolated ligand color reference

Side view of the yellow molecular membrane slab — **Membrane side view**Bilayer organization

Top view of the yellow molecular membrane slab — **Membrane top view**Planar environment

RECORDED MOTION

Available animations

The videos show the recorded trajectory segment at two scales. Contacts and displacements must be evaluated from quantitative data, not from the animations alone.

System-scale motion CB1R–THC dynamics in the membrane Read receptor geometry and ligand position within the modeled membrane environment.

Orthosteric-pocket motion Green THC within the CB1R orthosteric binding pocket Inspect ligand placement inside the receptor cavity and its local geometry without treating the animation alone as proof of binding stability.

COMPUTATIONAL WORKFLOW

Computational method, records, and limits by stage

Select a stage to see what was performed, what is available, and what the result cannot establish.

STRUCTURAL PROVENANCE

5XRA structure used for receptor preparation

The local computational directory identifies 5XRA as the receptor source. Its construct, mutations, fragment coverage, and original ligand context remain part of the interpretation.

Evidence statusSource identified; construct, mutations, and fragment coverage remain part of the interpretation.

NPT-STAGE MEASUREMENTS

Temperature, volume, and contacts between 302 and 400 ps

The NPT stage allows the simulation cell to respond while temperature and pressure are controlled. Move through the checkpoints extracted from the local analysis to compare volume, temperature, the Z dimension of the simulation box, and THC–CB1R contacts. Box height includes the membrane and solvent; it is not a measurement of bilayer thickness.

Analysis checkpoint

302 ps400 ps

Checkpoint 1 · 302 ps

Values are reported checkpoints from the files summary.TEMP, summary.VOLUME, box_dimensions.dat, and contacts_count.dat. The box and contact records are indexed by analysis frame.

Temperature310.11 Ktarget: 310 K

Volume948,550.14 Å³reported system volume

Box Z94.30 Åanalysis frame 1

Contacts131 / 0native / non-native

RESULTS REGISTER

Results available in the local files

These values summarize the local record. Verification requires the topology, coordinates, trajectory, and execution files; the docking score is not a measured binding affinity.

DOCKING SCORE−11.21

kcal·mol⁻¹ · Vina pose 1

ANALYSIS WINDOW300–400

ps · preliminary trajectory record

TARGET TEMPERATURE310

K · equilibration target

NEUTRALIZATION14 Cl⁻

0 M added salt concentration

System build97,244 atoms

declashed system record; a separate final build contains 98,718 atoms.

Backbone RMSD≈ 0.20–0.22 Å

reported in the inspected 300–400 ps window.

THC heavy-atom RMSD≈ 0.27 Å

after CB1R fit in the same window.

Contact definitionInitial pose

the “native” reference is computational, not experimental.

TECHNICAL REVIEW

Open issues that limit model validation

The files form a traceable preliminary record. Biological interpretation remains limited until preparation choices and sampling have been reviewed.

DOCUMENTED

Available records

5XRA-derived receptor and THC docking outputs.
Mixed-lipid membrane system with TIP3P water.
Minimization, heating, NPT, and semi-isotropic stages.
RMSD, RMSF, contact, ligand, and box analyses.

VERIFY BEFORE CLAIMING

What remains open

Confirm CYS154–CYS161 in the final topology; it is declared in the preparation record.
Review protonation because automatic protonation was skipped.
Separate neutralization ions from a physiological salt protocol.
Resolve receptor-file mismatch between docking configuration and log.
Establish production sampling, replicas, and convergence.

USES AND EVIDENCE LIMITS

Appropriate applications for this preliminary record

This record can be used to formulate hypotheses about ligand recognition and receptor motion. Evaluating those hypotheses requires experimental assays, longer sampling, and independent simulations.

RESEARCH

Formulation of structure–activity hypotheses

Computational models can organize hypotheses about recognition, selectivity, conformational change, and ligand–receptor contacts before experimental testing.

INDUSTRY

Documented comparison of poses and interactions

Curated structural records can support comparison of poses and interactions, documentation of analytical decisions, and reproducible research-and-development workflows. They do not, by themselves, establish compound efficacy.

PUBLIC SCIENCE

Separation of simulation and experiment

Identifying the source of each claim distinguishes simulated results, experimental results, and biological inferences.

INTERPRETIVE SCOPE

Conclusions supported by each evidence layer

Docking proposes a pose hypothesis. Binding affinity and residence time require dedicated experimental or validated computational evidence.

A 300–400 ps analysis window characterizes short-timescale behavior; long-timescale convergence and a unique binding mode require longer, replicated analyses.

5XRA is the local structural source and documents an AM11542-bound experimental context. Evidence for crystallized THC requires a structure obtained with THC under documented experimental conditions.

Read the CB1R molecular-dynamics context · Read the docking interpretation

Preparation and preliminary analysis of the membrane CB1R–THC system