A3.2

Question 1 Single best answer 1 point

A structure’s energy breakdown, in kcal/mol: bonds \(+2\), angles \(+3\), torsions \(+9\), van der Waals \(+40\), electrostatic \(-28\), total \(+26\). One torsion is twisted far from its usual value, and a Lys and an Asp side chain have atoms closer than their contact distance. All else is normal. Which feature accounts for the largest energy cost, and how does the total reflect that cost?

  1. The Lys-Asp contact: its van der Waals clash costs most, and the total reports that cost at its full size
  2. The Lys-Asp contact: its van der Waals clash costs most, and their attraction hides much of it in the total
  3. The twisted torsion: it costs most, since the Lys-Asp attraction hides that pair’s whole cost in the total
  4. The twisted torsion: it costs most, since the Lys-Asp pull is favorable, and the total reports its full size

Question 2 Single best answer 1 point

Which geometric feature of a structure does the angle term of an energy function score?

  1. The twist about a bond, set by four connected atoms
  2. The length of a bond, set by two connected atoms
  3. The angle between two bonds, set by three connected atoms
  4. The angle between two bonds, set by four connected atoms

Question 3 Single best answer 1 point

Two bonds share one force constant. One is lengthened past its reference length and the other shortened below its own, by equal small amounts. The shortened bond’s force constant is then halved. Which bond now has the higher bond-term energy, and why?

  1. Neither: the two started equal, and halving the force constant leaves the cost of an equal departure unchanged
  2. The shortened one: a squeezed bond starts up a steep wall, which halving its force constant cannot offset
  3. The lengthened one: the two started equal, and halving the force constant halves the shortened bond’s energy
  4. The lengthened one: the two started equal, and halving the force constant quarters the shortened bond’s energy

Question 4 Single best answer 1 point

On a peptide’s energy surface, state X has the deeper lowest point and state Y the much wider valley. What do these two features say about which state is favored?

  1. Y is favored: a valley that much wider holds more molecules than a deeper, narrower one
  2. Not enough: a free energy counts the water around each state, not the width of its valley
  3. X is favored: the deeper minimum has the lower free energy, so it holds more molecules
  4. Not enough: a free energy also counts the arrangements in each valley, not only its floor

Question 5 Single best answer 1 point

A potential energy surface is drawn as one curve. What do its horizontal axis and its height report?

  1. A coordinate locating the atoms, and the lowest potential energy in the valley around that arrangement
  2. A coordinate locating the atoms, and the potential energy of that one arrangement
  3. Time along a simulation, and the potential energy of the molecule at each moment
  4. Progress of a reaction, and the average potential energy of the molecules at each stage

Question 6 Single best answer 1 point

An optimization stops and reports “converged” at a point that is uphill both ways along one direction and downhill both ways along another. Why could its convergence criterion be met there?

  1. The step size was too large, and a run that overshoots onto a point stalls there
  2. The point is a minimum along the run’s last direction, and the criterion checks only that direction
  3. The energy there is below the start’s, and the criterion checks only whether the energy has fallen
  4. The slope there is zero, and the criterion checks only whether the slope is below its limit

Question 7 Single best answer 1 point

With its fixed step size, a minimization on a parabola-shaped energy curve hops back and forth across the minimum, landing just as far away each time. What does a slightly larger step do, and a slightly smaller one?

  1. Larger, each hop overshoots farther than the last; smaller, the hops shrink until the run settles
  2. Larger, it keeps bouncing evenly, only wider; smaller, the hops shrink until the run settles
  3. Larger, the run reaches the minimum in fewer steps and settles; smaller, it keeps hopping, only more slowly
  4. Larger, it bounces evenly over a wider span; smaller, it bounces evenly over a narrower one

Question 8 Single best answer 1 point

An energy curve has a deep minimum on the left and a shallow one on the right, with the barrier top much nearer the shallow one. Two minimizations start close together, one on each side of the barrier top. Where does each end, and why?

  1. Both in the shallow minimum, since a run ends in whichever minimum lies the shortest distance from its start
  2. Both in the deep minimum, since a run that starts near a barrier top falls toward the lowest minimum on the curve
  3. Left start in the shallow minimum, right start in the deep, since each step moves the way the slope’s sign points
  4. Left start in the deep minimum, right start in the shallow, since a run steps only downhill from its start

Question 9 Single best answer 1 point

An aspartic protease with a bound inhibitor is prepared twice: the catalytic Asp pair’s one shared proton sits on chain A’s Asp in one preparation and on chain B’s in the other. The inhibitor lies nearer chain A’s Asp. Of the pair’s total charge, the inhibitor interaction energy, the Asp B-factors, and the resolution, which change between the preparations?

  1. The interaction energy and the B-factors change; the total charge and the resolution do not
  2. The interaction energy changes; the total charge, the B-factors, and the resolution do not
  3. The interaction energy, the B-factors, and the resolution change; the total charge does not
  4. The total charge, the interaction energy, the B-factors, and the resolution stay as they were

Question 10 Single best answer 1 point

In a prepared complex, a protonated Asp makes a hydrogen bond with a ligand’s carbonyl oxygen. The complex is prepared again with that Asp deprotonated, then minimized. What does the new model show at that contact, and why?

  1. A neutral Asp donating again, since minimizing moves a proton back onto a carboxylate oxygen, where the bond scores lower
  2. A charge of minus one and no hydrogen bond, since the carbonyl oxygen polarizes away from the new charge and stops accepting
  3. A neutral Asp donating again, since the energy function sets the carboxylate’s protonation from the pH before scoring it
  4. A charge of minus one and no hydrogen bond, since an acceptor oxygen now faces an acceptor oxygen, with no O-H between

Question 11 Single best answer 1 point

A dimeric enzyme has two equivalent His, one per subunit, that may share a single proton. Which experiment could show which His holds it, and why?

  1. A routine X-ray structure, since its file places every atom, the proton included
  2. Neutron diffraction, since neutrons give finer resolution than X-rays, fine enough to place one proton
  3. Neutron diffraction, since neutrons scatter from atomic nuclei, so the hydrogen becomes visible
  4. X-ray diffraction on a deuterated crystal, since deuterium scatters about as strongly as carbon

Question 12 Single best answer 1 point

An enzyme’s closed form lies below its open form by a free-energy gap. A mutation doubles that gap. How does the ratio of closed to open molecules change?

  1. It is multiplied by ten, since doubling the gap adds one more factor of ten
  2. It doubles, since twice the free-energy gap favors the closed form twice as strongly
  3. It rises, but by less than double, since the closed share is capped at all of the molecules
  4. It is squared, since twice the gap holds twice as many factors of ten

Question 13 Single best answer 1 point

Ligands A and B bind the same site on a protein, and B’s \(K_d\) is 100-fold higher than A’s. When the two compete at equal concentration, how do their binding constants \(K\), their potencies, and their shares of the protein compare?

  1. A’s are larger, but each by its own factor, since each one converts from the free energy in its own way
  2. A’s are larger, by 100-fold in \(K\) and potency but by less in share, since a share is capped at the whole protein
  3. B’s are larger, each by the same 100-fold, since a higher \(K_d\) marks the larger binding constant
  4. A’s are larger, each by the same 100-fold, since one free-energy difference sets all three

Question 14 Single best answer 1 point

A protein loop’s two conformations differ in free energy by a couple of kcal/mol. One force field puts each total in the thousands of kcal/mol. What does the gap do to their populations, and why?

  1. Their numbers stay close to even, since a gap that is a tiny fraction of each conformation’s energy barely tilts the balance
  2. One outnumbers the other many-fold, since the gap alone sets their ratio, however large the values on each side
  3. One outnumbers the other by about two to one, since a gap of a few kcal/mol is only a few times the thermal energy
  4. Which one is favored cannot be said, since a gap that small lies inside a force field’s typical error

Question 15 Single best answer 1 point

Two conformers are ranked by an energy difference slightly larger than the method’s error. A better method cuts the error to a third, and the difference stays the same. How well supported is the ranking now, and why?

  1. Supported, as it was before, since a difference beyond the error was already enough
  2. Still weak, since support is judged by the size of the difference, and the difference has not changed
  3. Nearer, but still weak, since the bar falls by less than the error does and stays above the difference
  4. Supported, since a smaller error lowers the bar, and the same difference now clears it

Question 16 Single best answer 1 point

A mutation is claimed to leave an enzyme’s active-site loop “in” rather than “out” in solution. The evidence: the mutation was built into the deposited “in” structure, which was then minimized, and the loop stayed “in”. What does this evidence show, and what would settle the claim?

  1. That the energy the mutant lost on minimizing measures how firmly it holds “in”; a larger fall would make the claim firmer
  2. That a run started “in” ends in its own basin, which says nothing about the loop in solution; NMR would measure that
  3. That the claim holds only if the mutant’s energy is below the wild type’s; comparing those two energies would settle it
  4. That the mutant’s loop sits “in” in solution, since its minimized structure kept it there; an X-ray structure of the mutant would confirm it

Question 17 Single best answer 1 point

A \(pK_a\) predictor typically misses by about one pK unit. For two His in a binding site, His X’s predicted \(pK_a\) lies several units above the working pH, and His Y’s lies a few tenths of a unit above it. Which of the two protonation assignments does the prediction settle?

  1. It settles Y as protonated but not X, since a predicted \(pK_a\) far from the pH carries the larger miss
  2. It settles both as protonated, since each predicted \(pK_a\) lies above the working pH, so each holds its proton
  3. It settles X as protonated but not Y, since Y’s true \(pK_a\) could lie on the other side of the pH
  4. It settles neither, since a \(pK_a\) inside a protein can shift by units, so no prediction fixes an assignment
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