Fig 1.
Crystal structures of IL-1R1 with three different ligands.
(A) IL-1R1/IL-1β (PDB entry: 4DEF), (B) IL-1R1/IL-1Ra (PDB entry: 1IRA), and (C) IL-1R1/AF10847 (PDB entry: 1G0Y) superimposed with IL-1R1 from IL-1R1/IL-1β. (D) Cartoon depiction of activated and inactive conformations of IL-1R1 with three types of ligands, i.e. IL-1β, IL-1Ra and AF10847. AF10847 was not shown for clarity.
Fig 2.
Mapping of IL-1R1 ectodomain conformations obtained from cMD and aMD simulations to the PC1 and PC2 subspace.
Six crystal structures from five PDB entries: 4GAF, 1G0Y, 4DEP (2 chains), 1ITB and 1IRA (denoted by black circles), were used in the PCA to determine the first two principal components. Green and red circles denote the first and final conformations from each simulation.
Fig 3.
Superposition of 25 representative conformations obtained from the hierarchy cluster analysis and spherical projection of the center of mass of the D3 domain with respect to the D1-D2 domain.
(A) The conformation colored in green is the IL-1R1 from the crystal structure (PDB entry: 4GAF). The D1-D2 domain was colored in grey while the D3 domain was colored in pink. All conformations were aligned to the D1-D2 domain of the crystal structure and the root-mean-square-deviations of the D1-D2 and the D3 domains were calculated accordingly. (B) Definition of the coordinate system was provided. Distributions of longitudinal and latitudinal angles were calculated based on the coordinate system. Conformations correspond to three crystal structures were labeled by their PDB entry names.
Fig 4.
Small molecule binding site determined by the Sitemap analysis in three different IL-1R1 conformations extracted from the crystal structures.
S1-S5 denote the binding site number in each conformation and the arrows point to their locations.
Table 1.
Dscore values, volume sizes, hydrophilic and hydrophobic areas of the five binding sites in three IL-1R1 crystal structures (PDB entries: 4GAF, 1IRA and 1G0Y) identified by the Sitemap program.
Fig 5.
Mapping of IL-1R1 conformations to the first two principal components derived from two different PCAs.
(A) PCA is based on the 1180 conformations generated from aMD simulations. Crystal structures were shown in blue circles. (B) The PCA is based on six crystal structures from five PDB entries: 4GAF, 1G0Y, 4DEP (2 chains), 1ITB and 1IRA (denoted by black circles). Representative conformations of the 25 cluster groups were shown in purple circles. Conformations discussed in the text were shown in green circles and labeled.
Fig 6.
Distributions of Dscore values, volume sizes of the binding sites determined by the Sitemap analysis using 25 representative conformations obtained from the hierarchy cluster analysis.
The vanilla color regions correspond to the binding sites with Dscore value ≥ 0.83.
Table 2.
Dscore values, Volume sizes of up to five binding sites identified by the Sitemap program in 25 representative IL-1R1 conformations determined by the hierarchy cluster analysis of 1180 aMD generated conformations.
Fig 7.
Locations of druggable sites in 25 representative conformations and their physicochemical properties determined by Sitemap.
(A-C), druggable sites (Dscore values ≥ 0.83) in 25 representative conformations. Consensus binding sites at P1(diamond), P2(square) and P3(circle) locations in all conformations were shown. (D) Distributions of the physicochemical properties of the druggable sites. Balance refers to the ratio of hydrophobic and hydrophilic properties at the binding site. The four red arrows point to the values corresponding to four druggable sites in the crystal structures.
Fig 8.
Druggble sites, mapping of conformations to PC1 and PC2 in conformations 289, 524, 496, and 903 and the small molecule hotspot at the P2 site of conformation 289.
(A-B), druggable sites (yellow points) in conformations 289, 524, 496, and 903 identified by the Sitemap analysis. (C) Mapping of conformations obtained from the cosolvent MD simulations to the PC1-PC2 subspace. (D) The small molecule binding hotspot (the mesh envelop shape) at the P2 site in conformation 289 from the cosolvent mapping analysis. The phenol probe molecules within the mesh envelop region in 12 conformations from the cosolvent MD simulations were shown.
Fig 9.
Distribution and trajectories of root-mean-square-deviations (RMSDs) of backbone atoms in the protein-ligand complexes from simulations.
(A) is the D1-D2 domain, (B) the D3 domain and (C) heavy atoms of the ligands. The initial conformation 289/ligands conformations were used as the reference structures. Chemical structures of the eight ligands are provided in (D).
Fig 10.
Mapping of IL-1R1 conformations obtained from different MD simulations to PC1/PC2 and PC1/PC3 subspaces.
IL-1R1 conformations were extracted from 15 ns aqueous MD, 4 ns cosolvent MD simulations, L951/289, L1882/289, L1192/289, L537/289, L1206/289, L3097/289, L154/289 and L3241/289 MD simulations and mapped to PC1-PC2 (A-C) and PC1-PC3 (D-E) subspaces.
Fig 11.
Mapping of IL-1R1 conformations (blue circles) obtained from the 4 ns cosolvent MD, 8 ns MD simulations of L951/289, L1882/289, L1192/289, L1206/289, L3097/289, L154/289 and L324/289 to PC1, PC2 and PC3.
Trajectory of 15 ns MD simulations from the ligand-free conformation 289 was shown in orange circles. Trajectory of L1882/289 after 4.8 ns was shown in red circles.
Fig 12.
Chemical structures of four compounds identified from in silico screening to the P2 site in conformation 289 and snapshots of the IL-1R1/ligand conformations at 2 ns of MD simulations.
L951, L1882, L1192 and L537 interact with IL-1R1 without significant deviations from their initial docked poses up to the 2 ns MD simulations. Residues in IL-1R1 interact with the ligands were shown in stick model and labelled. Hydrogen bonds were depicted in cyan dash lines.