Molecular docking: rigid and flexible docking methods MCQs With Answer

Molecular docking: rigid and flexible docking methods MCQs With Answer — This quiz set is designed for M.Pharm students to deepen understanding of molecular docking approaches used in drug discovery. The questions focus on principles distinguishing rigid and flexible docking, sampling algorithms, scoring functions, receptor and ligand preparation, treatment of side-chain and backbone flexibility, and advanced strategies such as induced-fit, ensemble docking, and rescoring with physics-based methods. Each MCQ emphasizes conceptual clarity and practical implications for lead identification and optimization, including limitations, validation metrics like RMSD, and best practices in workflow. The level targets application and analysis suitable for postgraduate pharmaceutical training.

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

• Rigid docking allows full movement of both ligand and receptor
• Rigid docking keeps the receptor conformation fixed while flexible docking allows ligand and/or receptor flexibility
• Rigid docking uses quantum mechanics while flexible docking uses classical mechanics
• Rigid docking always produces more accurate binding energies than flexible docking

Correct Answer: Rigid docking keeps the receptor conformation fixed while flexible docking allows ligand and/or receptor flexibility

Q2. Which of the following best describes ligand flexibility in docking?

• Ligand flexibility refers to changes only in the receptor side chains
• Ligand flexibility is the sampling of different conformations by rotating ligand rotatable bonds
• Ligand flexibility means changing the ligand’s identity during docking
• Ligand flexibility is irrelevant if the receptor is flexible

Correct Answer: Ligand flexibility is the sampling of different conformations by rotating ligand rotatable bonds

Q3. Which sampling algorithm is commonly associated with AutoDock for flexible ligand docking?

• Simulated annealing
• Lamarckian genetic algorithm
• Deterministic grid search
• Metropolis-Hastings MCMC

Correct Answer: Lamarckian genetic algorithm

Q4. What does RMSD measure in docking validation?

• The difference in binding free energies between two docking programs
• Root-mean-square deviation between predicted and reference ligand atom positions
• Rate of convergence of the docking algorithm
• Relative solvent accessibility of the binding site

Correct Answer: Root-mean-square deviation between predicted and reference ligand atom positions

Q5. Which approach specifically addresses receptor backbone rearrangements upon ligand binding?

• Soft docking
• Side-chain rotamer sampling
• Ensemble docking using multiple receptor conformations
• Rigid-body docking with fixed receptor

Correct Answer: Ensemble docking using multiple receptor conformations

Q6. What is “soft docking”?

• A method that increases the van der Waals radii to prevent clashes
• A technique that uses reduced van der Waals repulsion or softened potentials to allow minor overlaps
• A procedure to dock covalent inhibitors only
• An approach that freezes ligand torsions to speed computation

Correct Answer: A technique that uses reduced van der Waals repulsion or softened potentials to allow minor overlaps

Q7. Which scoring function component estimates desolvation and hydrophobic contributions?

• Electrostatic Coulomb term
• Conformational entropy term
• Implicit solvent/desolvation term or hydrophobic term
• Bond stretching term

Correct Answer: Implicit solvent/desolvation term or hydrophobic term

Q8. Why are rotamer libraries used in flexible receptor docking?

• To enumerate ligand tautomers
• To provide a limited, biologically relevant set of side-chain conformations for sampling
• To force the backbone into a set of fixed conformations
• To increase the number of rotatable bonds in the ligand

Correct Answer: To provide a limited, biologically relevant set of side-chain conformations for sampling

Q9. Which of the following is a limitation of rigid docking?

• Impossible to perform on large proteins
• It cannot account for induced-fit changes in the binding site
• It always overestimates binding affinity
• It requires quantum mechanical calculations for each pose

Correct Answer: It cannot account for induced-fit changes in the binding site

Q10. What is cross-docking used for in docking studies?

• Docking a ligand back into its co-crystallized receptor only
• Evaluating docking performance by docking ligands into different receptor conformations
• Combining docking with MD simulation in a single step
• Docking only covalent inhibitors

Correct Answer: Evaluating docking performance by docking ligands into different receptor conformations

Q11. Which procedure improves accuracy after initial docking by calculating more rigorous binding energies?

• Rigid docking
• Grid-based fast scoring
• Rescoring with MM-GBSA or MM-PBSA
• Increasing the number of rotatable bonds

Correct Answer: Rescoring with MM-GBSA or MM-PBSA

Q12. Which term describes docking when the binding site is not known and the whole protein surface is searched?

• Focused docking
• Blind docking
• Ensemble docking
• Fragment-based docking

Correct Answer: Blind docking

Q13. In induced-fit docking protocols, what typically changes during the simulation?

• Only ligand protonation state changes
• Receptor side chains and sometimes backbone adjust to ligand binding
• Only water positions are optimized
• Only ligand chirality is altered

Correct Answer: Receptor side chains and sometimes backbone adjust to ligand binding

Q14. Which metric threshold is commonly used to consider a docking pose as successfully reproducing a crystal ligand pose?

• RMSD < 0.5 Å
• RMSD < 2.0 Å
• Binding energy < -5 kcal/mol
• Ligand heavy-atom count < 20

Correct Answer: RMSD < 2.0 Å

Q15. Which of the following improves sampling of ligand conformations during docking?

• Reducing the number of rotatable bonds artificially
• Using exhaustive systematic search for very small ligands or stochastic algorithms for larger ligands
• Switching off all scoring functions
• Rigidifying the receptor completely

Correct Answer: Using exhaustive systematic search for very small ligands or stochastic algorithms for larger ligands

Q16. Why is protonation state assignment important prior to docking?

• Protonation states determine ligand color in visualization software
• They influence charge distribution and hydrogen-bonding patterns, affecting binding pose and score
• They only affect conformational entropy calculations
• They are irrelevant if using a rigid receptor

Correct Answer: They influence charge distribution and hydrogen-bonding patterns, affecting binding pose and score

Q17. What benefit does consensus scoring provide in virtual screening?

• It guarantees the correct binding mode for every ligand
• Combining multiple scoring functions reduces false positives and improves hit selection
• It makes docking runs faster
• It eliminates the need for receptor preparation

Correct Answer: Combining multiple scoring functions reduces false positives and improves hit selection

Q18. Which docking strategy explicitly models formation of a covalent bond between ligand and target?

• Non-covalent flexible docking
• Covalent docking
• Blind docking
• Soft docking

Correct Answer: Covalent docking

Q19. When is inclusion of explicit water molecules in the binding site most justified?

• When water mediates key hydrogen bonds between ligand and receptor or is conserved in crystal structures
• When performing blind docking across the whole protein surface
• When ligand is completely hydrophobic and does not form H-bonds
• Only when doing rigid docking

Correct Answer: When water mediates key hydrogen bonds between ligand and receptor or is conserved in crystal structures

Q20. Which statement best describes ensemble docking?

• Docking a ligand into a single rigid receptor conformation using multiple scoring functions
• Docking ligands into multiple receptor conformations (from MD, NMR, or multiple crystal structures) to account for receptor flexibility
• Docking only fragments instead of full ligands
• Docking that excludes hydrophobic interactions from scoring

Correct Answer: Docking ligands into multiple receptor conformations (from MD, NMR, or multiple crystal structures) to account for receptor flexibility

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