Three sets of Boresch restraints were selected initially for pose A (Figure ). The first was the best-scoring set (B1) based on the minimum-variance algorithm, and mimics the phenol-Asn97C hydrogen bond (Figure ). To test varied anchor point positions, the second set (B2) was selected as the top-scoring restraints with anchor points outwith the phenol moiety -these were based on the triazole ring and were 7th best-scoring overall. Finally, selection was constrained to the quinoline moiety (B3). The parameters of restraint sets B1, B2, and B3 are given in Table . The protein anchor points were located in residues with low root-mean-square fluctuations (RMSFs) of the α-carbon positions although this was not directly targeted by the algorithm (Figure ). B1-poseB was the highest scoring set of A discussion of the challenges faced during restraint selection, symmetry corrections, and the strengths and limitations of the restraint selection algorithm is given in Section S6. Improvements to the restraints selection algorithm are also proposed -in particular, we recommend scoring possible restraints using a metric calculated from the variances of the DoF of the prospective restraints, rather than using the total variances directly. a Results for binding pose A, in kcal mol -1 . Uncertainties stated as 95 % confidence intervals based on the variance of 5 replicate runs, assuming Gaussian distributions. Restraint parameters are given in Table . -10 and -20 denote that all force constants were set to 10 or 20 kcal mol -1 Å-2 [rad -2 ], respectively. * Run 1 excluded from average due to under-sampling of water in binding site during the vanishing stage. ** Due to simulations crashing, results based on 4 independent replicates with partial completion of many lambda windows.