Homology modeling and protein 3D structure generation MCQs With Answer

Homology modeling and protein 3D structure generation MCQs With Answer

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Introduction: Homology modeling and protein 3D structure generation are essential topics in computer-aided drug design for M.Pharm students. This blog presents targeted multiple-choice questions to strengthen conceptual understanding and practical skills needed to build, evaluate, and apply homology models. Topics covered include template selection, sequence alignment, loop and side-chain modeling, model refinement, validation metrics, and common software tools. Emphasis is placed on interpreting quality scores, recognizing limitations of comparative modeling, and integrating models into docking and dynamics workflows. These MCQs are crafted to deepen knowledge required for research projects and coursework, enabling students to critically assess model reliability for drug discovery applications.

Q1. Which percentage sequence identity between target and template is generally considered the minimum for reliable homology modeling without extensive manual intervention?

  • Less than 20% sequence identity
  • 20–30% sequence identity
  • 30–50% sequence identity
  • Greater than 90% sequence identity

Correct Answer: 30–50% sequence identity

Q2. In comparative modeling, which step most critically determines whether insertions and deletions (indels) will be modeled accurately?

  • Energy minimization after model building
  • Accuracy of target-template sequence alignment
  • Side-chain rotamer selection
  • Choice of scoring function for model ranking

Correct Answer: Accuracy of target-template sequence alignment

Q3. Which program is widely used for automated comparative modeling using spatial restraints derived from templates?

  • AutoDock
  • MODELLER
  • GROMACS
  • BLAST

Correct Answer: MODELLER

Q4. Which validation metric primarily assesses the stereochemical quality of backbone phi/psi angles in a protein model?

  • Root-mean-square deviation (RMSD)
  • DOPE score
  • Ramachandran plot statistics
  • Binding free energy estimate

Correct Answer: Ramachandran plot statistics

Q5. The DOPE (Discrete Optimized Protein Energy) score is best described as:

  • A measure of electrostatic interactions only
  • A statistical potential assessing overall model quality
  • A docking score for ligand binding
  • A sequence alignment similarity metric

Correct Answer: A statistical potential assessing overall model quality

Q6. Which approach is preferred when no suitable template is available for a target protein?

  • Comparative modeling using a distant template
  • Protein threading/fold recognition
  • Ab initio (de novo) structure prediction
  • Homology modeling with multiple templates

Correct Answer: Ab initio (de novo) structure prediction

Q7. What is the primary advantage of using multiple templates in homology modeling?

  • Reduces computational time dramatically
  • Ensures a unique single conformation for the model
  • Combines complementary structural information to improve model accuracy
  • Avoids the need for sequence alignment

Correct Answer: Combines complementary structural information to improve model accuracy

Q8. Which of the following measures compares a model to the template(s) and quantifies structural deviation?

  • DOPE Z-score
  • RMSD (root-mean-square deviation)
  • Chi-squared test
  • Hamming distance

Correct Answer: RMSD (root-mean-square deviation)

Q9. Which tool specifically evaluates residue environment compatibility by comparing 3D structure with sequence-derived expected environments (1D-3D consistency)?

  • Verify3D
  • MolProbity
  • Clustal Omega
  • VMD

Correct Answer: Verify3D

Q10. During loop modeling, which method is most appropriate for short loops (<8 residues) when a high-resolution template is available?

  • Extensive ab initio sampling with molecular dynamics
  • Database search for loop fragments followed by grafting and local refinement
  • Ignore loops as they are unimportant for function
  • Random coil generation without refinement

Correct Answer: Database search for loop fragments followed by grafting and local refinement

Q11. Which scoring function is commonly used to assess statistical likelihood of a model derived from comparative modeling platforms like MODELLER?

  • BLAST e-value
  • GA341 score
  • pKa prediction score
  • Hydropathy index

Correct Answer: GA341 score

Q12. Which refinement technique can improve side-chain packing and relieve steric clashes after initial model building?

  • Side-chain rotamer optimization and short restrained energy minimization
  • Sequence alignment re-run without structural refinement
  • Only global ab initio folding
  • Removing all nonpolar residues

Correct Answer: Side-chain rotamer optimization and short restrained energy minimization

Q13. For membrane proteins, what special consideration should be included during homology modeling?

  • Ignore lipid environment because it does not affect structure
  • Include membrane-mimetic restraints or use membrane-aware modeling protocols
  • Always model in water-only implicit solvent
  • Use regular soluble-protein rotamer libraries without adjustment

Correct Answer: Include membrane-mimetic restraints or use membrane-aware modeling protocols

Q14. Which validation tool provides a statistical Z-score indicating whether a model’s overall energy is within the range of native proteins?

  • ProSA-web
  • Swiss-PDB Viewer
  • AutoDock Vina
  • HHpred

Correct Answer: ProSA-web

Q15. When incorporating a known ligand from the template into the homology model, what is a key risk that must be addressed?

  • Ligand always improves model quality so no checks are needed
  • Template ligand may force incorrect side-chain conformations or clash with target residues if alignment is poor
  • Ligands have no effect on active site geometry
  • Ligand transfer automatically corrects loop positions

Correct Answer: Template ligand may force incorrect side-chain conformations or clash with target residues if alignment is poor

Q16. Which metric is more robust than raw RMSD for comparing local model similarity to native structures across different protein lengths?

  • Sequence identity percentage
  • GDT-TS (Global Distance Test—Total Score)
  • BLAST bit score
  • Number of hydrogen bonds

Correct Answer: GDT-TS (Global Distance Test—Total Score)

Q17. What is the typical role of restrained molecular dynamics (MD) in model refinement?

  • To completely refold the protein from scratch
  • To apply distance and positional restraints while allowing relaxation of local stereochemistry and packing
  • To increase RMSD deliberately
  • To remove the template from the model

Correct Answer: To apply distance and positional restraints while allowing relaxation of local stereochemistry and packing

Q18. Which resource or database is most commonly used to find potential template structures for comparative modeling?

  • PDB (Protein Data Bank)
  • PubMed
  • UniProt sequence text file only
  • KEGG pathway maps

Correct Answer: PDB (Protein Data Bank)

Q19. In homology modeling workflows, what is the primary purpose of generating multiple candidate models (ensembles)?

  • To deliberately increase uncertainty in predictions
  • To sample conformational variability and identify models with better scoring and stereochemistry
  • To reduce computational cost compared to producing a single model
  • To bypass validation steps

Correct Answer: To sample conformational variability and identify models with better scoring and stereochemistry

Q20. Which factor most limits the accuracy of predicted binding modes when using homology models for structure-based docking?

  • High-resolution crystal structure of the template
  • Poor modeling of side-chain conformations and flexible loops in the binding site
  • Using the correct rotamer library
  • Including explicit water molecules during docking

Correct Answer: Poor modeling of side-chain conformations and flexible loops in the binding site

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