Supporting information

Binding affinities of the
SAMPL3 trypsin and host–guest blind tests
estimated with the MM/PBSA and LIE methods

Paulius Mikulskis 1, Samuel Genheden 1*, Patrik Rydberg 2,
Lars Sandberg3, Lars Olsen2, Ulf Ryde1

1 Department of Theoretical Chemistry, Lund University, Chemical Centre, P. O. Box 124,
SE-221 00 Lund, Sweden

2 Biostructural Research, Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark

3 Innovative Medicines, AstraZeneca R&D, SE-151 85 Södertälje, Sweden

Table S1. Affinities for the binding of ligands L35–L38 in Figure S1 to trypsin (kJ/mol), using either a charged or neutralised protein. The affinities were obtained with the MM/GBSA method.

Charged / Neutralised / Experiment
L35 / -108.3 / ±1.0 / -102.0 / ±1.6 / -27.6
L36 / -28.0 / ±2.3 / -40.8 / ±1.2 / -17.8
L37 / -37.3 / ±0.9 / -35.5 / ±2.0 / -21.2
L38 / -74.6 / ±2.0 / -74.3 / ±1.3 / -17.2

Table S2. Affinities for the binding of ligands G21–G29 in Figure 4 to host1 (kJ/mol), using different protonation states for the host. The affinities were obtained with the MM/GBSA method.

0 / –2 / –4 / Experiment
G21 / -156.5 / ±0.5 / -159.6 / ±0.4 / -160.2 / ±0.4 / -49.4 / ±0.2
G23 / -138.9 / ±3.5 / -150.7 / ±1.7 / -155.1 / ±1.5 / -32.6 / ±0.3
G27 / -135.2 / ±1.8 / -142.3 / ±1.8 / -138.9 / ±1.5 / -35.3 / ±0.2
G29 / -227.2 / ±2.2 / -217.1 / ±1.9 / -206.0 / ±1.4 / -53.7 / ±0.2
MADtr / 25.9 / ±1.0 / 19.3 / ±0.8 / 15.1 / ±0.6
τ / 0.67 / ±0.13 / 0.67 / ±0.08 / 0.67 / ±0.06
r2 / 0.70 / ±0.03 / 0.65 / ±0.02 / 0.63 / ±0.02

Figure S1 – Starting structure for the host2–G9 complex, illustrating the binding mode of the guests to host2 and host3.


Figure S2 – Ligands to trypsin and guests to host1 that were not a part of Sampl3 but were used as tests for the simulation setup. The black circle shows which part of the trypsin ligands that was directed towards Asp189.