Introduction: Flexible docking techniques MCQs With Answer introduce B. Pharm students to dynamic computational methods that model ligand and receptor flexibility during molecular recognition. Emphasizing key concepts—ligand flexibility, receptor conformational changes, sampling algorithms, scoring functions, induced-fit docking, ensemble docking, rotamer libraries, and free energy rescoring—this concise guide links theory to practical tools like AutoDock, Glide, GOLD and MM-GBSA. Students will learn how sampling strategies (Monte Carlo, molecular dynamics) and scoring limitations affect accuracy, selectivity, and computational cost. These focused MCQs reinforce protocol design, validation metrics (RMSD, enrichment), water/ion handling, and troubleshooting for drug-design projects. Now let’s test your knowledge with 30 MCQs on this topic.
Q1. What is the primary difference between rigid and flexible docking?
- Rigid docking allows movement in both ligand and receptor
- Flexible docking treats the ligand as flexible but keeps receptor fixed
- Flexible docking accounts for conformational changes in ligand and/or receptor
- Rigid docking uses molecular dynamics while flexible docking uses static scoring
Correct Answer: Flexible docking accounts for conformational changes in ligand and/or receptor
Q2. Which sampling method explicitly simulates time-dependent motions for exploring flexible conformations?
- Genetic algorithms
- Molecular dynamics (MD)
- Rotamer library sampling
- Grid-based scoring
Correct Answer: Molecular dynamics (MD)
Q3. What is an induced-fit docking approach intended to model?
- Only ligand tautomerization
- Post-docking free energy calculations
- Mutations in the receptor sequence
- Mutual adaptation of ligand and receptor conformations
Correct Answer: Mutual adaptation of ligand and receptor conformations
Q4. Which term describes systematic variation of rotatable bonds in a ligand?
- Conformational pruning
- Torsional sampling
- Consensus scoring
- Soft docking
Correct Answer: Torsional sampling
Q5. Which scoring method combines molecular mechanics energies with implicit solvation to estimate binding free energy?
- Empirical scoring
- MM-GBSA
- Knowledge-based potentials
- Grid score
Correct Answer: MM-GBSA
Q6. What does RMSD measure in docking validation?
- Root mean square deviation of atomic charges
- Geometric deviation between predicted and experimental ligand poses
- Difference in binding free energy estimates
- Computational time variability
Correct Answer: Geometric deviation between predicted and experimental ligand poses
Q7. Ensemble docking improves modeling of receptor flexibility by:
- Using multiple ligand tautomers only
- Docking ligands into a set of receptor conformations
- Restricting all receptor side chains to a single rotamer
- Removing solvent entirely from the binding site
Correct Answer: Docking ligands into a set of receptor conformations
Q8. Which technique perturbs side-chain conformations using predefined libraries during docking?
- Soft docking
- Rotamer sampling
- Pharmacophore modeling
- ALOHA sampling
Correct Answer: Rotamer sampling
Q9. Soft docking refers to:
- Using low-resolution protein structures only
- Allowing limited steric overlap by softening van der Waals potentials
- Docking in the absence of hydrogen atoms
- Docking exclusively with polar interactions
Correct Answer: Allowing limited steric overlap by softening van der Waals potentials
Q10. Which algorithm is commonly used to explore large ligand conformational spaces with stochastic moves and selection?
- Deterministic grid search
- Genetic algorithm
- Analytical minimization
- Principal component analysis
Correct Answer: Genetic algorithm
Q11. In flexible receptor docking, what is the main challenge compared to ligand flexibility?
- Receptor flexibility decreases accuracy
- Sampling combinatorial explosion of protein conformations
- Ligands cannot be protonated
- Docking scores are not used
Correct Answer: Sampling combinatorial explosion of protein conformations
Q12. Which practical strategy reduces computational cost while addressing receptor flexibility?
- Docking without scoring
- Using an ensemble of representative conformations derived from MD or crystal structures
- Removing all water molecules permanently
- Rigid docking followed by visual inspection only
Correct Answer: Using an ensemble of representative conformations derived from MD or crystal structures
Q13. What role do water molecules often play in flexible docking?
- They are always removed for accuracy
- They can mediate ligand–receptor interactions and must be considered selectively
- They only increase computational errors and should be ignored
- They convert ligands into covalent inhibitors
Correct Answer: They can mediate ligand–receptor interactions and must be considered selectively
Q14. Which metric evaluates early recognition of actives in virtual screening?
- RMSD
- AUC (Area Under the ROC Curve)
- Binding enthalpy
- Rotamer count
Correct Answer: AUC (Area Under the ROC Curve)
Q15. Covalent docking differs from non-covalent flexible docking because it must model:
- Only hydrogen bonds
- Formation of a covalent bond between ligand and target residue
- Protein unfolding
- Water exchange dynamics exclusively
Correct Answer: Formation of a covalent bond between ligand and target residue
Q16. What is rescoring in docking workflows?
- Rerunning the same docking program twice
- Applying a different, often more accurate scoring method to top poses
- Changing protonation states randomly
- Converting docked ligands to peptides
Correct Answer: Applying a different, often more accurate scoring method to top poses
Q17. Knowledge-based scoring functions are derived from:
- Quantum mechanical calculations for each complex
- Statistical analysis of known protein–ligand complexes
- Visual inspection by experts only
- Random number generation
Correct Answer: Statistical analysis of known protein–ligand complexes
Q18. Which parameter directly indicates the number of rotatable bonds affecting ligand flexibility?
- Root mean square deviation
- Torsional degrees of freedom
- pKa value
- Solubility
Correct Answer: Torsional degrees of freedom
Q19. In induced-fit protocols, which step commonly follows initial ligand placement?
- Sequence alignment
- Protein side-chain or backbone relaxation around the ligand
- Conversion to 2D structure
- Permanent removal of polar residues
Correct Answer: Protein side-chain or backbone relaxation around the ligand
Q20. Monte Carlo sampling in docking uses which of the following concepts?
- Time integration of Newtonian equations only
- Random perturbations accepted or rejected by a probability criterion
- Exclusive use of quantum tunneling
- Deterministic gradient descent without randomness
Correct Answer: Random perturbations accepted or rejected by a probability criterion
Q21. Which software is widely known for supporting flexible ligand docking and uses Lamarckian genetic algorithm?
- GOLD
- AutoDock
- ROSETTA
- OpenBabel
Correct Answer: AutoDock
Q22. Consensus scoring aims to improve docking reliability by:
- Using multiple scoring functions and combining their results
- Running the same scorer multiple times on the same pose
- Eliminating entropic contributions completely
- Only considering hydrogen bonds
Correct Answer: Using multiple scoring functions and combining their results
Q23. When docking metal-containing active sites, what extra consideration is crucial?
- Ignoring coordination geometry
- Modeling metal coordination and partial charges accurately
- Converting metals into dummy atoms
- Using only knowledge-based scores
Correct Answer: Modeling metal coordination and partial charges accurately
Q24. What is the benefit of using enhanced sampling (e.g., accelerated MD) in flexible docking workflows?
- It guarantees experimental binding energy predictions
- It accelerates exploration of rare but relevant conformations
- It removes the need for scoring functions
- It fixes protonation states permanently
Correct Answer: It accelerates exploration of rare but relevant conformations
Q25. Which validation metric assesses ability of a docking method to reproduce known poses within a small threshold?
- Enrichment factor
- RMSD with a cutoff (e.g., ≤2 Å)
- Partition coefficient
- pIC50 prediction
Correct Answer: RMSD with a cutoff (e.g., ≤2 Å)
Q26. Why is protonation state assignment important in flexible docking?
- Protonation states do not affect docking outcomes
- They determine hydrogen-bonding, electrostatics and ligand–receptor interactions
- They only influence color rendering in visualization
- They set the number of rotatable bonds to zero
Correct Answer: They determine hydrogen-bonding, electrostatics and ligand–receptor interactions
Q27. Which approach helps account for entropic contributions approximately after docking?
- Counting rotatable bonds or using MM-GBSA with entropy estimates
- Only using empirical scoring without adjustments
- Eliminating all waters
- Freezing the ligand in a single conformation
Correct Answer: Counting rotatable bonds or using MM-GBSA with entropy estimates
Q28. Which outcome indicates overfitting in a docking-scoring workflow?
- High predictive performance on independent test sets
- Excellent performance on training data but poor performance on new compounds
- Consistent ranking across multiple scoring functions
- Physically plausible binding modes for diverse ligands
Correct Answer: Excellent performance on training data but poor performance on new compounds
Q29. What is the main advantage of flexible fragment-based docking over full-ligand docking?
- Fragments eliminate the need for scoring
- Fragments reduce conformational complexity and can be grown or linked to improve sampling
- Fragments always bind covalently
- Fragments require quantum mechanics for every step
Correct Answer: Fragments reduce conformational complexity and can be grown or linked to improve sampling
Q30. Which practice improves reproducibility and credibility of docking studies in publications?
- Not reporting software versions or parameters
- Reporting docking protocols, parameters, protein preparation, and validation metrics
- Only showing highest-scored pose images without methods
- Using proprietary methods without detail
Correct Answer: Reporting docking protocols, parameters, protein preparation, and validation metrics
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