Molecular docking: rigid, flexible and extra-precision docking MCQs With Answer

Molecular docking: rigid, flexible and extra-precision docking MCQs With Answer

Introduction: Molecular docking is a cornerstone technique in computer-aided drug design that predicts how small molecules bind to target macromolecules. This quiz set focuses on distinctions between rigid, flexible, and extra-precision (XP) docking approaches, covering sampling algorithms, scoring functions, receptor and ligand flexibility, and practical considerations like water, protonation states, and rescoring methods. The questions are designed for M.Pharm students to deepen understanding of methodologies (e.g., grid-based docking, induced fit, ensemble docking), evaluation metrics (RMSD, enrichment), and advanced workflows (MM-GBSA rescoring, XP docking strategies) used to improve pose prediction and virtual screening outcomes.

Q1. What is the primary difference between rigid docking and flexible docking?

• Rigid docking treats both ligand and receptor as fixed bodies during pose generation.
• Rigid docking allows full receptor side-chain movement while keeping the ligand fixed.
• Flexible docking treats ligand as fixed and only samples receptor backbone conformation.
• Flexible docking samples ligand conformations and can allow receptor side-chain flexibility.

Correct Answer: Flexible docking samples ligand conformations and can allow receptor side-chain flexibility.

Q2. In docking terminology, what does the term “pose” refer to?

• The computed binding free energy of a ligand-receptor pair.
• The three-dimensional orientation and conformation of a ligand in the binding site.
• The set of all possible protonation states considered during docking.
• A clustering metric used to rank docking results.

Correct Answer: The three-dimensional orientation and conformation of a ligand in the binding site.

Q3. What is the main advantage of extra-precision (XP) docking over standard precision docking?

• XP docking uses a simpler scoring function for faster screening of millions of compounds.
• XP docking applies more stringent sampling, advanced scoring terms and penalties to reduce false positives.
• XP docking ignores hydrogen bonds to speed up calculations.
• XP docking only works for rigid protein structures and is less accurate for flexible sites.

Correct Answer: XP docking applies more stringent sampling, advanced scoring terms and penalties to reduce false positives.

Q4. Which metric is commonly used to evaluate how well a predicted pose matches an experimental ligand conformation?

• Binding affinity (IC50) prediction error.
• Root-mean-square deviation (RMSD) of heavy atoms between predicted and experimental poses.
• Number of rotatable bonds in the ligand.
• Docking score rank position among screened compounds.

Correct Answer: Root-mean-square deviation (RMSD) of heavy atoms between predicted and experimental poses.

Q5. Which of the following best describes induced-fit docking?

• A method that assumes both ligand and receptor are completely rigid.
• A procedure that allows iterative adjustment of receptor side-chains and ligand conformation during docking.
• Docking against multiple unrelated proteins to identify off-targets.
• Rescoring poses using empirical pKa predictions.

Correct Answer: A procedure that allows iterative adjustment of receptor side-chains and ligand conformation during docking.

Q6. Grid-based docking algorithms precompute which of the following to accelerate ligand placement?

• Solutions of the Schrödinger equation for the binding pocket.
• Energy or potential maps of receptor interaction potentials at discrete grid points.
• Full molecular dynamics trajectories of the receptor.
• Exact quantum mechanical electron densities for each residue.

Correct Answer: Energy or potential maps of receptor interaction potentials at discrete grid points.

Q7. Why is protonation state of ionizable groups important in docking?

• Protonation state affects ligand conformational entropy only, not interactions.
• Protonation determines hydrogen-bond donors/acceptors and charge interactions that influence binding geometry and score.
• Docking algorithms automatically ignore protonation differences, so it is irrelevant.
• Only the receptor protonation matters; ligand protonation can be neglected.

Correct Answer: Protonation determines hydrogen-bond donors/acceptors and charge interactions that influence binding geometry and score.

Q8. What is the role of rescoring with MM-GBSA after docking?

• To generate ligand tautomers and stereoisomers before docking.
• To refine and approximate binding free energies using molecular mechanics and implicit solvent for better ranking of top poses.
• To convert docking scores into pKa values for bound ligands.
• To reduce computational cost by replacing docking entirely.

Correct Answer: To refine and approximate binding free energies using molecular mechanics and implicit solvent for better ranking of top poses.

Q9. What is cross-docking in the context of docking studies?

• Docking a ligand into the same receptor conformation used to crystallize that ligand.
• Docking multiple ligands sequentially to predict toxic metabolites.
• Docking ligands into different receptor conformations (e.g., from other complexes) to evaluate robustness of predicted binding modes.
• Docking using cross-validation to tune scoring function parameters.

Correct Answer: Docking ligands into different receptor conformations (e.g., from other complexes) to evaluate robustness of predicted binding modes.

Q10. Which of the following is a limitation of rigid docking?

• It requires extensive sampling of ligand conformations which increases runtime dramatically.
• It cannot account for receptor conformational changes that are essential for correct ligand binding.
• It always overestimates binding affinity for polar ligands.
• It is only applicable to peptides and cannot dock small molecules.

Correct Answer: It cannot account for receptor conformational changes that are essential for correct ligand binding.

Q11. In flexible ligand docking, which molecular property is most often explicitly sampled?

• Protein backbone dihedrals exclusively.
• Ligand rotatable bonds and low-energy conformers.
• The ionization state of protein side-chains.
• Global unfolding of the receptor domain.

Correct Answer: Ligand rotatable bonds and low-energy conformers.

Q12. Which scoring function component is particularly emphasized in extra-precision (XP) docking to penalize unrealistic poses?

• Simple van der Waals attraction without penalties.
• Hydrophobic burial term with no desolvation penalty.
• Explicit penalties for steric clashes, unsatisfied hydrogen bond donors/acceptors, and desolvation mismatch.
• Only the molecular weight of the ligand as a penalty term.

Correct Answer: Explicit penalties for steric clashes, unsatisfied hydrogen bond donors/acceptors, and desolvation mismatch.

Q13. Ensemble docking is primarily used to address which problem?

• Inaccurate ligand parameterization for small molecules.
• Multiple receptor conformations and dynamic binding site flexibility.
• Slow convergence of docking algorithms due to grid size.
• Overfitting of scoring functions to training sets.

Correct Answer: Multiple receptor conformations and dynamic binding site flexibility.

Q14. Which of the following is a common approach to include explicit water molecules in docking?

• Remove all water molecules and ignore hydration effects entirely.
• Include conserved water molecules in the binding site as part of the receptor during docking.
• Convert water molecules into hydrophobic spheres to speed calculations.
• Replace water molecules with high-dielectric regions in the grid.

Correct Answer: Include conserved water molecules in the binding site as part of the receptor during docking.

Q15. What does a docking enrichment metric (e.g., ROC-AUC) measure in virtual screening?

• The binding free energy of each ligand in kcal/mol.
• The ability of the docking protocol to prioritize known actives over decoys early in the ranked list.
• The exact number of hydrogen bonds formed in the top pose.
• The computational time required per docking calculation.

Correct Answer: The ability of the docking protocol to prioritize known actives over decoys early in the ranked list.

Q16. Why are rotatable bonds in a ligand important to control before docking?

• They determine the ligand’s solubility in organic solvents only.
• They influence conformational sampling complexity and the number of possible poses to evaluate.
• They do not affect docking; only ring systems matter.
• They only impact pharmacokinetics, not binding poses.

Correct Answer: They influence conformational sampling complexity and the number of possible poses to evaluate.

Q17. In Glide terminology, which docking mode is typically used for high-throughput virtual screening?

• Extra-precision (XP) for screening millions of ligands as the fastest option.
• Standard precision (SP) or high-throughput virtual screening (HTVS) modes for initial filtering due to speed.
• Induced Fit Docking exclusively for library screening of millions of compounds.
• MM-GBSA mode as the only screening mode in Glide.

Correct Answer: Standard precision (SP) or high-throughput virtual screening (HTVS) modes for initial filtering due to speed.

Q18. What is a practical reason to perform ligand clustering after docking?

• To increase the docking score of all poses artificially.
• To reduce redundancy by grouping similar poses and identify diverse binding modes for further analysis.
• To automatically assign protonation states to ligands.
• To eliminate the need for rescoring or visual inspection.

Correct Answer: To reduce redundancy by grouping similar poses and identify diverse binding modes for further analysis.

Q19. Which statement about scoring functions is correct?

• All scoring functions reliably predict absolute binding free energies within 0.1 kcal/mol.
• Empirical, knowledge-based, and physics-based scoring functions exist; each has strengths and weaknesses for ranking vs absolute prediction.
• Scoring functions are unnecessary if you use flexible docking.
• Quantum mechanical scoring is universally superior and always used in high-throughput docking.

Correct Answer: Empirical, knowledge-based, and physics-based scoring functions exist; each has strengths and weaknesses for ranking vs absolute prediction.

Q20. What is a common sign that a docking pose may be unreliable despite a favorable score?

• The pose shows reasonable hydrogen bonding and complementary shape but low molecular weight.
• The pose includes severe steric clashes, unrealistic torsion angles, or buried polar groups without compensating interactions.
• The ligand has a single aromatic ring and no rotatable bonds.
• The docking score is lower than other ligands in the set.

Correct Answer: The pose includes severe steric clashes, unrealistic torsion angles, or buried polar groups without compensating interactions.

G S Sachin

I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.

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