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Relationships between Th1 or Th2 iNKT cell activity and structures of CD1d-antigen complexes: meta-analysis of CD1d-glycolipids dynamics simulations.

Laurent X, Renault N, Farce A, Chavatte P, Hénon E - PLoS Comput. Biol. (2014)

Bottom Line: A number of potentially bioactive molecules can be found in nature.Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects.One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response.

View Article: PubMed Central - PubMed

Affiliation: Intestinal Biotech Development, Faculté de Médecine, Lille, France; Laboratoire de Chimie Thérapeutique EA4481, Université Lille 2, Lille, France.

ABSTRACT
A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an α-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius). Very rapidly, a synthetic glycololipid analogue of this natural molecule was discovered, called KRN7000. Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects. In our work, we carried out molecular dynamics simulations (11.5 µs in total) involving eight different ligands (conducted in triplicate) in an effort to find out correlation at the molecular level, if any, between chemical modulation of 1 and the orientation of the known biological response, Th1 or Th2. Comparative investigations of human versus mouse and Th1 versus Th2 data have been carried out. A large set of analysis tools was employed including free energy landscapes. One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response. These theoretical tools provide a structural basis for predicting the very different dynamical behaviors of α-glycosphingolipids in CD1d and might aid in the future design of new analogues of 1.

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3D-FEL associated to the polar head conformations for the H_aGAL system.Left: 1 loaded human CD1d with the OTAN hydrogen bond network emphasized and the three torsion angles for the polar head to be rotated. Right: 3D-free energy representations of H_aGAL system 1 (replica I, T = 300K); each of the nine isosurfaces corresponds to points of the 3D-space (φx, φy, φz) with a constant free energy isovalue (in kcal.mol−1); the three last boxes correspond to the three isosurfaces (2.7 kcal.mol−1) obtained for the three replicas (240 ns each).
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pcbi-1003902-g006: 3D-FEL associated to the polar head conformations for the H_aGAL system.Left: 1 loaded human CD1d with the OTAN hydrogen bond network emphasized and the three torsion angles for the polar head to be rotated. Right: 3D-free energy representations of H_aGAL system 1 (replica I, T = 300K); each of the nine isosurfaces corresponds to points of the 3D-space (φx, φy, φz) with a constant free energy isovalue (in kcal.mol−1); the three last boxes correspond to the three isosurfaces (2.7 kcal.mol−1) obtained for the three replicas (240 ns each).

Mentions: Finally, the conformational space explored by the polar head of the ligand during the simulations of H_aGAL was described using the three torsion angles of the three successive rotatable bonds shown in Figure 6. In the following, the first one (φx) will be referred as the anomeric pivot, the second one (φy) as middle pivot and the last one (φz) will be denoted the amide axis. Theoretically, rotations around φx and φz yield conformations in which the polar head has rotated horizontally at the top of the cavity entrance. In the CD1d environment, these two motions should be hardly sterically hindered by the two helices. In contrast, rocking about the middle pivot will get the polar head striking the helices. In all cases, such individual rotations would require the loss of the OTAN H-bond network. The free energy landscape of the MD trajectory along these three coordinates is illustrated in Figure 6 for the system Sy1. The top panel shows all points in the (φx, φy, φz) space with isovalues of G being one to nine kBT (0.6 to 5.3 kcal.mol−1) for replica I of H_aGAL. For all simulations, the conformational space does not grow any more for energies above 9 kBT. For replica I, the 3D-FEL emphasizes only one conformational state, showing that the OTAN network is strong enough to maintain the orientation during all the 240ns simulation. This state, hereafter referred to as “OTAN state”, is centered about the φx, φy, φz coordinates: (50°, 157°, 51°) in replica I. Comparison with the three replicas of H_aGAL at G = 5.3 kcal.mol−1 (9 kBT, bottom panel of Figure 5) reveals the presence of the OTAN state in every case. But in addition, two secondary conformational states can be visited, mainly limited to the (φx, φz) plane. It is very important to note that, as with the OTAN state, these two complementary states maintain the polar head interacting with helix α2. Actually, the second state observed in replica II is a combination of two rotations about φx and φz that limits the displacement of the sugar ring (see Figure S3). The third state observed in replica III corresponds to a rotation of about 180° around φz, which brings again the polar head in contact with helix α2 (see Figure S4). In this last state, the Asp151 residue is now hydrogen-bonded to the 4′-OH group (sphingosine chain) and the Trp153 side chain is again in van der Waals (VDW) contact with the hydrophobic side of the polar head. But most importantly, no conformations are observed involving rotations about the middle pivot φy, points that would lie inside the 3D-FEL box, involving the “y” axis.


Relationships between Th1 or Th2 iNKT cell activity and structures of CD1d-antigen complexes: meta-analysis of CD1d-glycolipids dynamics simulations.

Laurent X, Renault N, Farce A, Chavatte P, Hénon E - PLoS Comput. Biol. (2014)

3D-FEL associated to the polar head conformations for the H_aGAL system.Left: 1 loaded human CD1d with the OTAN hydrogen bond network emphasized and the three torsion angles for the polar head to be rotated. Right: 3D-free energy representations of H_aGAL system 1 (replica I, T = 300K); each of the nine isosurfaces corresponds to points of the 3D-space (φx, φy, φz) with a constant free energy isovalue (in kcal.mol−1); the three last boxes correspond to the three isosurfaces (2.7 kcal.mol−1) obtained for the three replicas (240 ns each).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4222593&req=5

pcbi-1003902-g006: 3D-FEL associated to the polar head conformations for the H_aGAL system.Left: 1 loaded human CD1d with the OTAN hydrogen bond network emphasized and the three torsion angles for the polar head to be rotated. Right: 3D-free energy representations of H_aGAL system 1 (replica I, T = 300K); each of the nine isosurfaces corresponds to points of the 3D-space (φx, φy, φz) with a constant free energy isovalue (in kcal.mol−1); the three last boxes correspond to the three isosurfaces (2.7 kcal.mol−1) obtained for the three replicas (240 ns each).
Mentions: Finally, the conformational space explored by the polar head of the ligand during the simulations of H_aGAL was described using the three torsion angles of the three successive rotatable bonds shown in Figure 6. In the following, the first one (φx) will be referred as the anomeric pivot, the second one (φy) as middle pivot and the last one (φz) will be denoted the amide axis. Theoretically, rotations around φx and φz yield conformations in which the polar head has rotated horizontally at the top of the cavity entrance. In the CD1d environment, these two motions should be hardly sterically hindered by the two helices. In contrast, rocking about the middle pivot will get the polar head striking the helices. In all cases, such individual rotations would require the loss of the OTAN H-bond network. The free energy landscape of the MD trajectory along these three coordinates is illustrated in Figure 6 for the system Sy1. The top panel shows all points in the (φx, φy, φz) space with isovalues of G being one to nine kBT (0.6 to 5.3 kcal.mol−1) for replica I of H_aGAL. For all simulations, the conformational space does not grow any more for energies above 9 kBT. For replica I, the 3D-FEL emphasizes only one conformational state, showing that the OTAN network is strong enough to maintain the orientation during all the 240ns simulation. This state, hereafter referred to as “OTAN state”, is centered about the φx, φy, φz coordinates: (50°, 157°, 51°) in replica I. Comparison with the three replicas of H_aGAL at G = 5.3 kcal.mol−1 (9 kBT, bottom panel of Figure 5) reveals the presence of the OTAN state in every case. But in addition, two secondary conformational states can be visited, mainly limited to the (φx, φz) plane. It is very important to note that, as with the OTAN state, these two complementary states maintain the polar head interacting with helix α2. Actually, the second state observed in replica II is a combination of two rotations about φx and φz that limits the displacement of the sugar ring (see Figure S3). The third state observed in replica III corresponds to a rotation of about 180° around φz, which brings again the polar head in contact with helix α2 (see Figure S4). In this last state, the Asp151 residue is now hydrogen-bonded to the 4′-OH group (sphingosine chain) and the Trp153 side chain is again in van der Waals (VDW) contact with the hydrophobic side of the polar head. But most importantly, no conformations are observed involving rotations about the middle pivot φy, points that would lie inside the 3D-FEL box, involving the “y” axis.

Bottom Line: A number of potentially bioactive molecules can be found in nature.Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects.One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response.

View Article: PubMed Central - PubMed

Affiliation: Intestinal Biotech Development, Faculté de Médecine, Lille, France; Laboratoire de Chimie Thérapeutique EA4481, Université Lille 2, Lille, France.

ABSTRACT
A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an α-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius). Very rapidly, a synthetic glycololipid analogue of this natural molecule was discovered, called KRN7000. Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects. In our work, we carried out molecular dynamics simulations (11.5 µs in total) involving eight different ligands (conducted in triplicate) in an effort to find out correlation at the molecular level, if any, between chemical modulation of 1 and the orientation of the known biological response, Th1 or Th2. Comparative investigations of human versus mouse and Th1 versus Th2 data have been carried out. A large set of analysis tools was employed including free energy landscapes. One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response. These theoretical tools provide a structural basis for predicting the very different dynamical behaviors of α-glycosphingolipids in CD1d and might aid in the future design of new analogues of 1.

Show MeSH
Related in: MedlinePlus