Molecular mechanics and quantum mechanics in drug design MCQs With Answer

Molecular mechanics and quantum mechanics in drug design MCQs With Answer

by

Molecular mechanics and quantum mechanics in drug design MCQs With Answer

This collection of multiple-choice questions is tailored for M.Pharm students studying MPC 203T: Computer Aided Drug Design. The questions focus on the theoretical foundations and practical applications of molecular mechanics (MM) and quantum mechanics (QM) methods used in modern drug discovery. Topics include force fields, energy terms, parameterization, conformational sampling, QM methods (HF, DFT, post-HF), QM/MM hybrid approaches, charge models, and computational strategies for predicting binding and reactivity. Each question tests conceptual understanding and practical implications to help students prepare for exams and apply these methods in research settings.

Q1. Which term in a classical force field specifically describes the energy penalty for deviations from the preferred bond length?

  • Angle bending term
  • Dihedral torsion term
  • Bond stretching term
  • Nonbonded van der Waals term

Correct Answer: Bond stretching term

Q2. Which of the following is a primary advantage of quantum mechanical methods over molecular mechanics in drug design?

  • Significantly lower computational cost for large biomolecules
  • Ability to describe electronic structure changes such as bond breaking/forming
  • Built-in transferable parameters for every organic molecule
  • Faster conformational sampling of large systems

Correct Answer: Ability to describe electronic structure changes such as bond breaking/forming

Q3. In a force field functional form, the Lennard-Jones potential is mainly used to model which interaction?

  • Bond stretching between covalently bonded atoms
  • Electrostatic interactions between partial charges
  • Nonbonded van der Waals attraction and short-range repulsion
  • Angle bending around three-atom centers

Correct Answer: Nonbonded van der Waals attraction and short-range repulsion

Q4. Which quantum chemical method explicitly includes electron correlation beyond the Hartree–Fock mean-field approximation?

  • Hartree–Fock (HF)
  • Density Functional Theory (DFT)
  • Restricted Open-Shell HF (ROHF)
  • Molecular Mechanics (MM)

Correct Answer: Density Functional Theory (DFT)

Q5. Which partial charge assignment method is derived from fitting to the molecular electrostatic potential calculations?

  • Mulliken population analysis
  • RESP (Restrained Electrostatic Potential)
  • Gasteiger charges
  • Formal integer oxidation states

Correct Answer: RESP (Restrained Electrostatic Potential)

Q6. QM/MM hybrid methods are most useful in drug design for which of the following applications?

  • Rapid generation of conformer libraries for entire proteins
  • High-level treatment of an enzyme active site while treating the remainder classically
  • Replacing all classical force-field parameters with semi-empirical MM parameters
  • Exclusively predicting solvation free energies with implicit solvent models

Correct Answer: High-level treatment of an enzyme active site while treating the remainder classically

Q7. Which basis set change generally increases the accuracy of a QM calculation for describing electron density in anions or polar bonds?

  • Removing polarization functions
  • Using a minimal STO-3G basis set
  • Adding diffuse functions (e.g., +) to the basis set
  • Using only core-only basis functions

Correct Answer: Adding diffuse functions (e.g., +) to the basis set

Q8. Which of the following best describes the Born–Oppenheimer approximation used in most QM calculations?

  • Electrons and nuclei move on identical timescales
  • Nuclei are treated quantum mechanically while electrons are classical
  • Electronic motion is separated from nuclear motion because nuclei move much slower
  • All atoms are fixed; only electrons are optimized

Correct Answer: Electronic motion is separated from nuclear motion because nuclei move much slower

Q9. Which semi-empirical method is commonly used for rapid QM-level geometry optimizations in drug design workflows?

  • MP2 (Møller–Plesset perturbation theory)
  • AM1 or PM6 semi-empirical methods
  • Coupled cluster CCSD(T)
  • Full Configuration Interaction

Correct Answer: AM1 or PM6 semi-empirical methods

Q10. In molecular mechanics, which parameterization issue is most critical when modeling novel drug-like heterocycles?

  • Lack of empirical van der Waals radii for hydrogen
  • Absence of adequate torsional parameters and partial charges for novel ring systems
  • Overestimation of covalent bond orders by MM
  • Inability to model long-range electrostatics with cutoffs

Correct Answer: Absence of adequate torsional parameters and partial charges for novel ring systems

Q11. What does the HOMO–LUMO gap primarily indicate in QM-based drug design analyses?

  • The molecular mass of a ligand
  • Reactivity and chemical softness, with smaller gaps suggesting higher reactivity
  • The number of rotatable bonds in a molecule
  • The exact binding free energy to a target protein

Correct Answer: Reactivity and chemical softness, with smaller gaps suggesting higher reactivity

Q12. Which energy decomposition scheme is frequently used to estimate binding energies from molecular dynamics snapshots combined with MM energies?

  • Hartree–Fock energy decomposition
  • MM-PBSA or MM-GBSA methods
  • RESP charge decomposition
  • DFT-based energy partitioning exclusively

Correct Answer: MM-PBSA or MM-GBSA methods

Q13. Basis set superposition error (BSSE) is a concern in QM calculations of noncovalent complexes because it can cause which artifact?

  • Underestimation of van der Waals radii
  • Artificial stabilization (overestimation) of interaction energies
  • Complete failure to converge the SCF cycle
  • Incorrect prediction of nuclear spin states

Correct Answer: Artificial stabilization (overestimation) of interaction energies

Q14. Which DFT functional property is particularly important for accurately modeling dispersion (van der Waals) interactions without additional corrections?

  • Pure local density approximation without gradient dependence
  • Inclusion of long-range dispersion corrections or using dispersion-inclusive functionals
  • Using minimal basis sets only
  • Omitting exchange contributions entirely

Correct Answer: Inclusion of long-range dispersion corrections or using dispersion-inclusive functionals

Q15. During a conformational search using molecular mechanics, which algorithm is commonly used to find a global minimum across many local minima?

  • Steepest descent without restarts
  • Simulated annealing or Monte Carlo sampling combined with minimization
  • Single-point QM energy evaluation only
  • Analytical solution of the Schrödinger equation

Correct Answer: Simulated annealing or Monte Carlo sampling combined with minimization

Q16. Which of the following force fields is widely used and parametrized for proteins and nucleic acids in biomolecular simulations?

  • AMBER force field
  • PM3 semi-empirical Hamiltonian
  • CCSD(T)/aug-cc-pVTZ
  • RESP-LJ hybrid

Correct Answer: AMBER force field

Q17. When studying a proton transfer mechanism in an enzyme active site, which computational approach is most appropriate?

  • Pure classical molecular mechanics with fixed partial charges
  • QM/MM with the proton transfer region treated quantum mechanically
  • Empirical scoring functions only
  • Coarse-grained bead models of the entire protein

Correct Answer: QM/MM with the proton transfer region treated quantum mechanically

Q18. What is the primary limitation of Mulliken population analysis when used to assign atomic charges for use in force fields?

  • It always gives exactly zero partial charges
  • Strong basis-set dependence and sometimes counterintuitive charge distributions
  • It requires experimental dipole moments for calibration
  • It cannot be computed from Hartree–Fock wavefunctions

Correct Answer: Strong basis-set dependence and sometimes counterintuitive charge distributions

Q19. In drug design, why might one use a hybrid QM/MM free energy perturbation (FEP) calculation rather than pure MM-FEP?

  • To eliminate the need for sampling configurations
  • To allow electronic structure changes (e.g., ligand protonation or covalent bond formation) during the perturbation
  • Because QM/MM FEP is always faster than MM-FEP
  • To avoid calculating solvation contributions

Correct Answer: To allow electronic structure changes (e.g., ligand protonation or covalent bond formation) during the perturbation

Q20. Which computed property from QM calculations can be most directly used to predict sites of metabolism or nucleophilic/electrophilic attack on a drug molecule?

  • Classical force-field torsion profiles
  • Frontier molecular orbital densities and Fukui functions
  • Total molecular mass from MM
  • Empirical logP alone

Correct Answer: Frontier molecular orbital densities and Fukui functions

Leave a Comment